Zolmitriptan Nasal Spray is indicated for the acute treatment of migraine with or without aura in adults and pediatric patients 12 years of age and older.

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Limitations of Use:

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The recommended starting dose for zolmitriptan nasal spray in adult and pediatric patients 12 years of age and older is 2.5 mg. As the individual response to zolmitriptan nasal spray may vary, the dose should be adjusted on an individual basis. The maximum recommended single dose of zolmitriptan is 5 mg.

If the migraine has not resolved by 2 hours after taking zolmitriptan, or returns after a transient improvement, another dose may be administered at least 2 hours after the previous dose.

The maximum daily dose should not exceed 10 mg in any 24-hour period.

The safety of zolmitriptan in the treatment of an average of more than four headaches in a 30-day period has not been established.

Zolmitriptan nasal spray is not recommended in patients with moderate to severe hepatic impairment because of increased zolmitriptan blood levels in these patients and elevation of blood pressure in some of these patients. The recommended dosage of zolmitriptan nasal spray in patients with mild hepatic impairment is the same as for patients with normal hepatic function [see Dosage and Administration (2.1), Warnings and Precautions (5.8), Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].

If zolmitriptan is co-administered with cimetidine, limit the maximum single dose of zolmitriptan to 2.5 mg, not to exceed 5 mg in any 24-hour period [see Drug Interactions (7.4) and Clinical Pharmacology (12.3)].

Nasal Spray 2.5 mg and 5 mg.

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Zolmitriptan is contraindicated in patients with:

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Zolmitriptan is contraindicated in patients with ischemic or vasospastic coronary artery disease (CAD). There have been rare reports of serious cardiac adverse reactions, including acute myocardial infarction, occurring within a few hours following administration of zolmitriptan. Some of these reactions occurred in patients without known CAD. 5-HT1 agonists including zolmitriptan may cause coronary artery vasospasm (Prinzmetal’s Angina), even in patients without a history of CAD.

Perform a cardiovascular evaluation in triptan-naïve patients who have multiple cardiovascular risk factors (e.g., increased age, diabetes, hypertension, smoking, obesity, strong family history of CAD) prior to receiving zolmitriptan. Do not administer zolmitriptan if there is evidence of CAD or coronary artery vasospasm [see Contraindications (4)]. For patients with multiple cardiovascular risk factors who have a negative cardiovascular evaluation, consider administrating the first zolmitriptan dose in a medically-supervised setting and performing an electrocardiogram (ECG) immediately following zolmitriptan administration. For such patients, consider periodic cardiovascular evaluation in intermittent long-term users of zolmitriptan.

Life-threatening disturbances of cardiac rhythm including ventricular tachycardia and ventricular fibrillation leading to death have been reported within a few hours following the administration of 5-HT1 agonists. Discontinue zolmitriptan if these disturbances occur. Patients with Wolff-Parkinson-White Syndrome or arrhythmias associated with other cardiac accessory conduction pathway disorders should not receive zolmitriptan [see Contraindications (4)].

As with other 5-HT1 agonists, sensations of tightness, pain, pressure, and heaviness in the precordium, throat, neck, and jaw commonly occur after treatment with zolmitriptan and is usually non-cardiac in origin. However, if a cardiac origin is suspected, patients should be evaluated. Patients shown to have CAD and those with Prinzmetal’s variant angina should not receive 5-HT1 agonists [see Contraindications (4)].

Cerebral hemorrhage, subarachnoid hemorrhage, and stroke have occurred in patients treated with 5-HT1 agonists, and some have resulted in fatalities. In a number of cases, it appears possible that the cerebrovascular events were primary, the 5-HT1 agonist having been administered in the incorrect belief that the symptoms experienced were a consequence of migraine, when they were not. Discontinue zolmitriptan if a cerebrovascular event occurs.

As with other acute migraine therapies, before treating headaches in patients not previously diagnosed as migraineurs, and in migraineurs who present with symptoms atypical for migraine, other potentially serious neurological conditions should be excluded. Zolmitriptan should not be administered to patients with a history of stroke or transient ischemic attack [see Contraindications (4)].

5-HT1 agonists, including zolmitriptan, may cause non-coronary vasospastic reactions, such as peripheral vascular ischemia, gastrointestinal vascular ischemia and infarction (presenting with abdominal pain and bloody diarrhea), splenic infarction, and Raynaud’s syndrome. In patients who experience symptoms or signs suggestive of vasospasm reaction following the use of any 5-HT1 agonist, the suspected vasospasm reaction should be ruled out before receiving additional zolmitriptan doses [see Contraindications (4)].

Reports of transient and permanent blindness and significant partial vision loss have been reported with the use of 5-HT1 agonists. Since visual disorders may be part of a migraine attack, a causal relationship between these events and the use of 5-HT1 agonists have not been clearly established.

Overuse of acute migraine drugs (e.g. ergotamine, triptans, opioids, or a combination of drugs for 10 or more days per month) may lead to exacerbation of headache (medication overuse headache). Medication overuse headache may present as migraine-like daily headaches, or as a marked increase in frequency of migraine attacks. Detoxification of patients, including withdrawal of the overused drugs, and treatment of withdrawal symptoms (which often includes a transient worsening of headache) may be necessary.

Serotonin syndrome may occur with triptans, including zolmitriptan, particularly during co-administration with selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), and MAO inhibitors [see Drug Interactions (7.5)]. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). The onset of symptoms usually rapidly occurs within minutes to hours of receiving a new or a greater dose of a serotonergic medication. Zolmitriptan treatment should be discontinued if serotonin syndrome is suspected [see Drug Interactions (7.5) and Patient Counseling Information (17)].

Significant elevations in systemic blood pressure have been reported in patients treated with 5-HT1 agonists including patients without a history of hypertension. Very rarely these increases in blood pressure have been associated with significant clinical events. In healthy subjects treated with 5 mg of zolmitriptan oral tablet, an increase of 1 and 5 mm Hg in the systolic and diastolic blood pressure, respectively, was seen. In a study of patients with moderate to severe liver impairment, 7 of 27 patients experienced 20 to 80 mm Hg elevations in systolic and/or diastolic blood pressure after a dose of 10 mg of zolmitriptan oral tablet. As with all triptans, blood pressure should be monitored in zolmitriptan-treated patients. Zolmitriptan is contraindicated in patients with uncontrolled hypertension [see Contraindications (4)].

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.

Adults

Among 460 patients treating 1180 single attacks with zolmitriptan nasal spray in a blinded placebo controlled trial (Study 1), there was a low withdrawal rate related to adverse reactions: 5 mg (1.3%), 2.5 mg (0%), and placebo (0.4%). None of the withdrawals were due to a serious event. One patient was withdrawn due to abnormal ECG changes from baseline that were incidentally found 23 days after the last dose of zolmitriptan nasal spray.

The most common adverse reactions (≥ 5% and > placebo) in any dosage strength in clinical trials for zolmitriptan nasal spray were: unusual taste, paresthesia, hyperesthesia, and dizziness. The incidence of adverse reactions was generally dose-related.

Table 1 lists the adverse reactions from the controlled clinical trial (Study 1) that occurred in ≥ 2% of patients in either the 2.5 or 5 mg zolmitriptan nasal spray dose groups and with an incidence greater than placebo.

Table 1: Adverse reactions in a Placebo-Controlled Study in Adult Patients with Migraine (Study 1)

<div class="scrollingtable"><table width="100%"> <col width="41%"/> <col width="21%"/> <col width="19%"/> <col width="18%"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Body System</span> </p> <p>Adverse Reaction</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Placebo</span> </p> <p> <span class="Bold">(N=228)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Zolmitriptan</span> </p> <p> <span class="Bold">2.5 mg</span> </p> <p> <span class="Bold">(N=224)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Zolmitriptan</span> </p> <p> <span class="Bold">5 mg</span> </p> <p> <span class="Bold">(N=236)</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="4" valign="top"> <p class="First"> <span class="Bold">Atypical Sensations</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Hyperesthesia</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">5%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Paraesthesia</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">6%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">5%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">10%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Warm Sensation</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">4%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="4" valign="top"> <p class="First"> <span class="Bold">Ear/Nose/Throat</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Disorder/Discomfort of nasal cavity</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">3%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="4" valign="top"> <p class="First"> <span class="Bold">Pain and Pressure Sensations</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Pain Location Specified</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">4%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Throat Pain</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">4%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">4%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Throat Tightness</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">&lt;1%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="4" valign="top"> <p class="First"> <span class="Bold">Digestive</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Dry Mouth</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">&lt;1%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">3%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Nausea</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">4%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="4" valign="top"> <p class="First"> <span class="Bold">Neurological</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Dizziness</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">4%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">6%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">3%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Somnolence</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">4%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="4" valign="top"> <p class="First"> <span class="Bold">Other</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Unusual Taste</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">3%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">17%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">21%</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Asthenia</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">3%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">3%</p> </td> </tr> </tbody> </table></div>

In Study 1, adverse reactions occurring in ≥ 1% and < 2% of patients in all attacks in either zolmitriptan nasal spray dose group and with incidence greater than that of placebo were: abdominal pain, chills, throat pressure, facial edema, chest pressure, palpitation, dysphagia, arthralgia, myalgia, and depersonalization.

The incidence of adverse reactions in controlled clinical trials was not affected by gender, weight, or age of the patients (18-39 vs. 40-65 years of age), or presence of aura. There were insufficient data to assess the impact of race on the incidence of adverse reactions.

Local Adverse Reactions:

Among 460 patients using zolmitriptan 2.5 mg or 5 mg in the controlled clinical trial, approximately 3% noted local irritation or soreness at the site of administration. Adverse reactions of any kind, perceived in the nasopharynx (which may include systemic effects of triptans) were severe in about 1% of patients and approximately 57% resolved in 1 hour. Nasopharyngeal examinations, in a subset of patients participating in two long term trials of up to one-year duration, failed to demonstrate any clinically significant changes with repeated use of zolmitriptan nasal spray.

All nasopharyngeal adverse reactions with an incidence of ≥ 2% of patients in any zolmitriptan nasal spray dose groups are included in Table 1.

Other Adverse Reactions:

In the paragraphs that follow, the frequencies of less commonly reported adverse clinical reactions are presented. Because the reports include reactions observed in open and uncontrolled studies, the role of zolmitriptan in their causation cannot be reliably determined. Furthermore, variability associated with adverse reaction reporting, the terminology used to describe adverse reactions, etc., limit the value of the quantitative frequency estimates provided. Reaction frequencies are calculated as the number of patients who used zolmitriptan nasal spray and reported a reaction divided by the total number of patients exposed to zolmitriptan nasal spray (n=3059). All reported reactions are included except those already listed in the previous table, those too general to be informative, and those not reasonably associated with the use of the drug. Reactions are further classified within body system categories and enumerated in order of decreasing frequency using the following definitions: infrequent adverse reactions are those occurring in 1/100 to 1/1,000 patients and rare adverse reactions are those occurring in fewer than 1/1,000 patients.

General: Infrequent: allergic reactions.

Cardiovascular: Infrequent: arrhythmias, hypertension, syncope and tachycardia. Rare: angina pectoris and myocardial infarct.

Digestive: Rare: stomatitis.

Neurological: Infrequent: agitation, amnesia, anxiety, depression, insomnia, and nervousness. Rare: convulsions.

Respiratory: Infrequent: bronchitis, increased cough, dyspnea, epistaxis, laryngeal edema, pharyngitis, rhinitis, and sinusitis.

Skin: Infrequent: pruritus, rash, and urticaria.

Urogenital: Infrequent: polyuria and urinary urgency. Rare: urinary frequency.

Special senses: Infrequent: tinnitus. Rare: conjunctivitis, dry eye, and visual field defect.

The adverse reaction profile seen with zolmitriptan nasal spray is similar to that seen with zolmitriptan tablets and zolmitriptan oral disintegrating tablets except for the occurrence of local adverse reactions from the nasal spray.

Pediatric Patients 12 to 17 Years of Age

The safety of zolmitriptan nasal spray in the acute treatment of migraine in pediatric patients 12 to 17 years of age was established in two studies [see Pediatric Use (8.4) and Clinical Studies (14.2)].

The most common adverse reactions (incidence of ≥ 2% of pediatric patients receiving 2.5 mg and 5 mg zolmitriptan nasal spray and numerically greater than placebo) after a single dose are summarized in Table 2. Dysgeusia (unusual taste) was the most common adverse reaction, with a numerically greater incidence for patients receiving zolmitriptan compared to placebo (10% vs. 2%). Other common adverse reactions were nasal discomfort, dizziness, oropharyngeal pain, and nausea.

Table 2 lists the adverse reactions from the pooled placebo-controlled studies that occurred in ≥ 2% of pediatric patients 12 to 17 years of age in either the 2.5 mg or 5 mg zolmitriptan dose groups and with an incidence greater than placebo.

Table 2: Adverse reactions in Pooled Placebo-Controlled Studies in Pediatric Patients 12 to 17 years of Age with Migraine

<div class="scrollingtable"><table width="100%"> <col width="24%"/> <col width="24%"/> <col width="25%"/> <col width="25%"/> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Adverse Reaction</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Placebo</span> </p> <p> <span class="Bold">(N=437)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Zolmitriptan</span> </p> <p> <span class="Bold">2.5 mg</span> </p> <p> <span class="Bold">(N=81)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Zolmitriptan</span> </p> <p> <span class="Bold">5 mg</span> </p> <p> <span class="Bold">(N=431)</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Unusual taste</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">6%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">10%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Nasal discomfort</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">3%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">3%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Dizziness</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Oropharyngeal pain</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2%</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Nausea</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2%</p> </td> </tr> </tbody> </table></div>

The adverse reaction profile was similar across gender. There were insufficient data to assess the impact of race on the incidence of adverse reactions.

The following adverse reactions were identified during post approval use of zolmitriptan. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

The reactions enumerated include all except those already listed in the Clinical Trials Experience section above or the Warnings and Precautions section.

Hypersensitivity Reactions:

There have been reports of anaphylaxis, anaphylactoid, and hypersensitivity reactions including angioedema in patients receiving zolmitriptan. Zolmitriptan is contraindicated in patients with a history of hypersensitivity reaction to zolmitriptan.

Ergot-containing drugs have been reported to cause prolonged vasospastic reactions. Because these effects may be additive, use of ergotamine-containing or ergot-type medications (like dihydroergotamine or methysergide) and zolmitriptan within 24 hours of each other is contraindicated [see Contraindications (4)].

MAO-A inhibitors increase the systemic exposure of zolmitriptan. Therefore, the use of zolmitriptan in patients receiving MAO-A inhibitors is contraindicated [see Contraindications (4) and Clinical Pharmacology (12.3)].

Concomitant use of other 5-HT1B/1D agonists (including triptans) within 24 hours of zolmitriptan treatment is contraindicated because the risk of vasospastic reactions may be additive [see Contraindications (4)].

Following administration of cimetidine, the half-life and AUC of zolmitriptan and its active metabolites were approximately doubled [see Clinical Pharmacology (12.3)]. If cimetidine and zolmitriptan are used concomitantly, limit the maximum single dose of zolmitriptan to 2.5 mg, not to exceed 5 mg in any 24-hour period [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)].

Cases of life-threatening serotonin syndrome have been reported during combined use of selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs) and triptans [see Warnings and Precautions (5.7)].

Risk Summary

There are no adequate data on the developmental risk associated with the use of zolmitriptan in pregnant women. In reproductive toxicity studies in rats and rabbits, oral administration of zolmitriptan to pregnant animals resulted in embryolethality and fetal abnormalities (malformations and variations) at clinically relevant exposures (see Data).

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. The estimated rates of major birth defects (2.2%-2.9%) and miscarriage (17%) among deliveries to women with migraine are similar to rates reported in women without migraine.

Clinical Considerations

Disease-Associated Maternal and/or Embryo/Fetal Risk

Published data have suggested that women with migraine may be at increased risk of preeclampsia during pregnancy.

Data

Animal Data

When zolmitriptan was administered to pregnant rats during the period of organogenesis at oral doses of 100, 400, and 1200 mg/kg/day (plasma exposures (AUCs) ≈280, 1100, and 5000 times the human AUC at the maximum recommended human dose (MRHD) of 10 mg/day), there was a dose-related increase in embryolethality. A no-effect dose for embryolethality was not established. When zolmitriptan was administered to pregnant rabbits during the period of organogenesis at oral doses of 3, 10, and 30 mg/kg/day (plasma AUCs ≈1, 11, and 42 times the human AUC at the MRHD), there were increases in embryolethality and in fetal malformations and variations. The no-effect dose for adverse effects on embryo-fetal development was associated with a plasma AUC similar to that in humans at the MRHD. When female rats were given zolmitriptan during gestation, parturition, and lactation at oral doses of 25, 100, and 400 mg/kg/day (plasma AUCs ≈70, 280, and 1100 times that in human at the MRHD), an increased incidence of hydronephrosis was found in the offspring. The no-effect dose was associated with a plasma AUC ≈280 times that in humans at the MRHD.

Risk Summary

There are no data on the presence of zolmitriptan or its metabolites in human milk, the effects on the breastfed infant, or the effects of zolmitriptan and its metabolites on milk production. In rats, oral dosing with zolmitriptan resulted in levels in milk up to 4 times that in maternal plasma.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for zolmitriptan and any potential adverse effects on the breastfed infant from zolmitriptan or from the underlying maternal condition.

Safety and effectiveness of zolmitriptan in pediatric patients under 12 years of age have not been established.

The efficacy of zolmitriptan nasal spray in the acute treatment of migraine in pediatric patients 12 to 17 years of age was established in a placebo-controlled study with a total of 81 pediatric patients receiving zolmitriptan 2.5 mg and 229 pediatric patients receiving zolmitriptan 5 mg [see Clinical Studies (14.2)].

In an earlier study with a different design, zolmitriptan 5 mg nasal spray was evaluated in the acute treatment of migraine headache in 171 pediatric patients 12 to 17 years of age. In that study, the efficacy of zolmitriptan nasal spray was not established.

The safety of zolmitriptan nasal spray in the acute treatment of migraine in pediatric patients 12 to 17 years of age was established in two placebo-controlled studies with a total of 81 pediatric patients receiving zolmitriptan 2.5 mg and 431 pediatric patients receiving zolmitriptan 5 mg [see Adverse Reactions (6.1)].

The safety profile of zolmitriptan nasal spray in pediatric patients 12 to 17 years of age is similar to the profile observed in adults [see Adverse Reactions (6.1)].

In the postmarketing experience with triptans, including zolmitriptan, there is a limited number of reports that describe pediatric patients who have experienced clinically serious adverse events; those that were reported are similar in nature to those reported rarely in adults.

Clinical studies of zolmitriptan did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Geriatric patients who have other cardiovascular risk factors (e.g., diabetes, hypertension, smoking, obesity, strong family history of coronary artery disease) should have a cardiovascular evaluation prior to receiving zolmitriptan [see Warnings and Precautions (5.1)]. The pharmacokinetics of zolmitriptan were similar in geriatric patients (aged > 65 years) compared to younger patients [see Clinical Pharmacology (12.3)].

The effect of hepatic disease on the pharmacokinetics of zolmitriptan nasal spray has not been evaluated. After oral administration, zolmitriptan blood levels were increased in patients with moderate to severe hepatic impairment, and significant elevation in blood pressure was observed in some of these patients [see Warnings and Precautions (5.8)]. Zolmitriptan nasal spray is not recommended in patients with moderate to severe hepatic impairment [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)].

There is no experience with acute overdose. Clinical study subjects receiving single 50 mg oral doses of zolmitriptan commonly experienced sedation.

{ "type": "p", "children": [], "text": "There is no experience with acute overdose. Clinical study subjects receiving single 50 mg oral doses of zolmitriptan commonly experienced sedation." }

The elimination half-life of zolmitriptan is 3 hours [see Clinical Pharmacology (12.1)] and therefore monitoring of patients after overdose with zolmitriptan should continue for at least 15 hours or while symptoms or signs persist.

{ "type": "p", "children": [], "text": "The elimination half-life of zolmitriptan is 3 hours [see Clinical Pharmacology (12.1)] and therefore monitoring of patients after overdose with zolmitriptan should continue for at least 15 hours or while symptoms or signs persist." }

There is no specific antidote to zolmitriptan. In cases of severe intoxication, intensive care procedures are recommended, including establishing and maintaining a patent airway, ensuring adequate oxygenation and ventilation, and monitoring and support of the cardiovascular system.

{ "type": "p", "children": [], "text": "There is no specific antidote to zolmitriptan. In cases of severe intoxication, intensive care procedures are recommended, including establishing and maintaining a patent airway, ensuring adequate oxygenation and ventilation, and monitoring and support of the cardiovascular system." }

It is unknown what effect hemodialysis or peritoneal dialysis has on the plasma concentrations of zolmitriptan.

{ "type": "p", "children": [], "text": "It is unknown what effect hemodialysis or peritoneal dialysis has on the plasma concentrations of zolmitriptan." }

Zolmitriptan Nasal Spray, USP contains zolmitriptan, which is a selective 5-hydroxytryptamine 1B/1D (5-HT1B/1D) receptor agonist. Zolmitriptan is chemically designated as (S)-4-[[3-[2-(dimethylamino)ethyl]-1H-indol-5-yl]methyl]-2-oxazolidinone and has the following chemical structure:

{ "type": "p", "children": [], "text": "Zolmitriptan Nasal Spray, USP contains zolmitriptan, which is a selective 5-hydroxytryptamine 1B/1D (5-HT1B/1D) receptor agonist. Zolmitriptan is chemically designated as (S)-4-[[3-[2-(dimethylamino)ethyl]-1H-indol-5-yl]methyl]-2-oxazolidinone and has the following chemical structure:" }

The empirical formula is C16H21N3O2, representing a molecular weight of 287.36. Zolmitriptan is a white to almost white powder that is readily soluble in water. Zolmitriptan Nasal Spray is supplied as a clear to pale yellow solution of zolmitriptan, buffered to a pH 5.0. Each Zolmitriptan Nasal Spray contains 2.5 mg or 5 mg of zolmitriptan in a 100-μL unit dose aqueous buffered solution containing citric acid, anhydrous, USP, disodium phosphate dodecahydrate USP, benzalkonium chloride solution NF and purified water USP.

{ "type": "p", "children": [], "text": "The empirical formula is C16H21N3O2, representing a molecular weight of 287.36. Zolmitriptan is a white to almost white powder that is readily soluble in water. Zolmitriptan Nasal Spray is supplied as a clear to pale yellow solution of zolmitriptan, buffered to a pH 5.0. Each Zolmitriptan Nasal Spray contains 2.5 mg or 5 mg of zolmitriptan in a 100-μL unit dose aqueous buffered solution containing citric acid, anhydrous, USP, disodium phosphate dodecahydrate USP, benzalkonium chloride solution NF and purified water USP." }

Zolmitriptan Nasal Spray is hypertonic. The osmolarity of Zolmitriptan Nasal Spray for 2.5 mg is 358 to 396 mOsmol, and for 5 mg is 411 to 455 mOsmol.

{ "type": "p", "children": [], "text": "Zolmitriptan Nasal Spray is hypertonic. The osmolarity of Zolmitriptan Nasal Spray for 2.5 mg is 358 to 396 mOsmol, and for 5 mg is 411 to 455 mOsmol." }

Zolmitriptan binds with high affinity to human recombinant 5-HT1D and 5-HT1B receptors, and moderate affinity for 5-HT1A receptors. The N-desmethyl metabolite also has high affinity for 5-HT1B/1D and moderate affinity for 5-HT1A receptors.

Current theories proposed to explain the etiology of migraine headache suggest that symptoms are due to local cranial vasodilatation and/or to the release of sensory neuropeptides (vasoactive intestinal peptide, substance P and calcitonin gene-related peptide) through nerve endings in the trigeminal system. The therapeutic activity of zolmitriptan for the treatment of migraine headache is thought to be due to the agonist effects at the 5-HT1B/1D receptors on intracranial blood vessels (including the arterio-venous anastomoses) and sensory nerves of the trigeminal system which result in cranial vessel constriction and inhibition of pro-inflammatory neuropeptide release.

Absorption, Distribution, Metabolism, and Excretion

Absorption

Zolmitriptan nasal spray is rapidly absorbed via the nasopharynx as detected in a Photon Emission Tomography (PET) study using 11C zolmitriptan. The mean relative bioavailability of the nasal spray formulation is 102%, compared with the oral tablet. Zolmitriptan was detected in plasma by 5 minutes and peak plasma concentration generally was achieved by 3 hours. The time at which maximum plasma concentrations were observed was similar after single (1 day) or multiple (4 days) nasal dosing. Plasma concentrations of zolmitriptan are sustained for 4 to 6 hours after dosing. Zolmitriptan and its active N-desmethyl metabolite display linear kinetics after single or multiple doses of zolmitriptan nasal spray over the dose range of 0.1 to 10 mg.

The pharmacokinetics of the N-desmethyl metabolite are similar to that of zolmitriptan for all nasal spray dosages. The N-desmethyl metabolite is detected in plasma by 15 minutes and peak plasma concentration is generally achieved by 3 hours after administration.

Food has no significant effect on the bioavailability of zolmitriptan.

Distribution

Plasma protein binding of zolmitriptan is 25% over the concentration range of 10-1000 ng/mL. The mean apparent volume of distribution for zolmitriptan nasal spray formulation is 8.4 L/kg.

Metabolism

Zolmitriptan is converted to an active N-desmethyl metabolite such that the metabolite concentrations are about two-thirds that of zolmitriptan. Because the 5HT1B/1D potency of the metabolite is 2 to 6 times that of the parent compound, the metabolite may contribute a substantial portion of the overall effect after zolmitriptan administration.

Excretion

The mean elimination half-life for zolmitriptan and N-desmethyl metabolite following single or multiple nasal spray administration are approximately 3 hours, similar to the half-life values seen after oral tablet administration.

In a study with orally administered zolmitriptan, total radioactivity recovered in urine and feces was 65% and 30% of the administered dose, respectively. In urine, unchanged zolmitriptan and N-desmethyl metabolite accounted for 8% and 4% of the dose, respectively, whereas the inactive indole acetic acid and N-oxide metabolites accounted for 31% and 7% of the dose, respectively.

Mean total plasma clearance for zolmitriptan nasal spray is 25.9 mL/min/kg, of which one-sixth is renal clearance. The renal clearance is greater than the glomerular filtration rate suggesting renal tubular secretion.

Specific Populations

Age:

The pharmacokinetics of orally administered zolmitriptan in healthy elderly non-migraineur volunteers (age 65-76 yrs) was similar to those in younger non-migraineur volunteers (age 18-39 yrs).

Sex:

Mean plasma concentrations of orally administered zolmitriptan were up to 1.5-fold higher in females than males.

Race:

There are no significant differences in the pharmacokinetics of orally administered zolmitriptan in Japanese and Caucasians.

Renal Impairment:

The effect of renal impairment on the pharmacokinetics of zolmitriptan nasal spray has not been evaluated. After orally dosing zolmitriptan, renal clearance was reduced by 25% in patients with severe renal impairment (Clcr ≥ 5 ≤ 25 mL/min) compared with the normal group (Clcr ≥ 70 mL/min); no significant change in clearance was observed in the moderately renally impaired group (Clcr ≥ 26 ≤ 50 mL/min).

Hepatic Impairment:

The effect of hepatic disease on the pharmacokinetics of zolmitriptan nasal spray has not been evaluated. In patients with severe hepatic impairment, the mean Cmax, Tmax, and AUC of zolmitriptan dosed orally were increased 1.5-fold, 2-fold (2 vs. 4 hours), and 3-fold, respectively, compared to subjects with normal hepatic function. Seven out of 27 patients experienced 20 to 80 mm Hg elevations in systolic and/or diastolic blood pressure after a 10 mg zolmitriptan dose [see Dosage and Administration (2.2) and Use in Specific Populations (8.6)].

Hypertensive Patients:

No differences in the pharmacokinetics of oral zolmitriptan or its effects on blood pressure were seen in mild to moderate hypertensive volunteers compared with normotensive controls.

Drug Interactions

All drug interaction studies were performed in healthy volunteers using a single 10 mg dose of zolmitriptan and a single dose of the other drug except where otherwise noted. Eight drug interaction studies have been performed with zolmitriptan tablets and one study (xylometazoline) was performed with nasal spray.

Xylometazoline:

An in vivo drug interaction study with zolmitriptan nasal spray indicated that 1 spray (100 μL dose) of xylometazoline (0.1% w/v), a decongestant, administered 30 minutes prior to a 5 mg nasal dose of zolmitriptan did not alter the pharmacokinetics of zolmitriptan.

Fluoxetine:

The pharmacokinetics of zolmitriptan, as well as its effect on blood pressure, were unaffected by 4 weeks of pre-treatment with oral fluoxetine (20 mg/day).

MAO Inhibitors:

Following one week of administration of moclobemide (150 mg twice-daily), a specific MAO-A inhibitor, there was an increase of about 25% in both Cmax and AUC for zolmitriptan and a 3-fold increase in the Cmax and AUC of the active N-desmethyl metabolite of zolmitriptan [see Contraindications (4) and Drug Interactions (7.2)].

Selegiline, a selective MAO-B inhibitor, at a dose of 10 mg/day for 1 week, had no effect on the pharmacokinetics of zolmitriptan and its metabolite.

Propranolol:

Cmax and AUC of zolmitriptan increased 1.5-fold after one week of dosing with propranolol (160 mg/day). Cmax and AUC of the N-desmethyl metabolite were reduced by 30% and 15%, respectively. There were no interactive effects on blood pressure or pulse rate following administration of propranolol with zolmitriptan.

Acetaminophen:

A single 1g dose of acetaminophen does not alter the pharmacokinetics of zolmitriptan and its N-desmethyl metabolite. However, zolmitriptan delayed the Tmax of acetaminophen by one hour.

Metoclopramide:

A single 10 mg dose of metoclopramide had no effect on the pharmacokinetics of zolmitriptan or its metabolites.

Oral Contraceptives:

Retrospective analysis of pharmacokinetic data across studies indicated that mean Cmax and AUC of zolmitriptan were 30% and 50% higher, respectively, and Tmax was delayed by one-half hour in females taking oral contraceptives compared to females not taking oral contraceptives. The effect of zolmitriptan on the pharmacokinetics of oral contraceptives has not been studied.

Cimetidine:

Following the administration of cimetidine, the half-life and AUC of a 5 mg dose of zolmitriptan and its active metabolite were approximately doubled. A dosage adjustment is therefore required [see Drug Interactions (7.4)].

Carcinogenesis

Zolmitriptan was administered to mice and rats at doses up to 400 mg/kg/day. Mice were dosed for 85 weeks (males) and 92 weeks (females); rats were dosed for 101 weeks (males) and 86 weeks (females). There was no evidence of drug-induced tumors in mice at plasma exposures (AUC) up to approximately 700 times that in humans at the maximum recommended human dose (MRHD) of 10 mg/day. In rats, there was an increase in the incidence of thyroid follicular cell hyperplasia and thyroid follicular cell adenomas in male rats receiving 400 mg/kg/day. No increase in tumors was observed in rats at 100 mg/kg/day, a dose associated with a plasma AUC≈700 times that in humans at the MRHD.

Mutagenesis

Zolmitriptan was positive in an in vitro bacterial reverse mutation (Ames) assay and in an in vitro chromosomal aberration assay in human lymphocytes. Zolmitriptan was negative in an in vitro mammalian gene cell mutation (CHO/HGPRT) assay and in oral in vivo micronucleus assays in mouse and rat.

Impairment of Fertility

Studies of male and female rats administered zolmitriptan prior to and during mating and up to implantation showed no impairment of fertility at oral doses up to 400 mg/kg/day. The plasma exposure (AUC) at this dose was approximately 3000 times that in humans at the MRHD.

The efficacy of zolmitriptan nasal spray 2.5 mg and 5 mg in the acute treatment of migraine headache with or without aura in adults was demonstrated in Study 1, a randomized, outpatient, double-blind, placebo-controlled trial.

In Study 1, patients were instructed to treat a moderate to severe headache. Headache response, defined as a reduction in headache severity from moderate or severe pain to mild or no pain, was assessed 15, 30, 45 minutes and 1, 2, and 4 hours after dosing. Pain-free response rates and associated symptoms such as nausea, photophobia, and phonophobia were also assessed. A dose of escape medication was allowed 4 to 24 hours after the initial treatment for persistent and recurrent headache.

In Study 1, of the patients taking zolmitriptan nasal spray 2.5 mg or 5 mg, 83% were female and 99% were Caucasian, with a mean age of 41 years (range 18 to 65 years).

The two-hour headache response rates in patients treated with zolmitriptan nasal spray were significantly higher among patients receiving zolmitriptan nasal spray at all doses, compared with placebo (see Table 3).

Table 3: First Attack Data: Percentage of Adult Patients with Headache Response to Zolmitriptan Nasal Spray (Mild or No Headache) 2 Hours Following Treatment in Study 1

<div class="scrollingtable"><table width="100%"> <col width="33%"/> <col width="33%"/> <col width="33%"/> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">PLACEBO</span> </p> <p> <span class="Bold">(N=218)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Zolmitriptan</span> </p> <p> <span class="Bold">2.5 mg</span> </p> <p> <span class="Bold">(N=219)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Zolmitriptan</span> </p> <p> <span class="Bold">5 mg</span> </p> <p> <span class="Bold">(N=228)</span> </p> </td> </tr> <tr class="Last"> <td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">31%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">55%*</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">69%*</p> </td> </tr> </tbody> </table></div>

*p < 0.001 in comparison with placebo

The estimated probability of achieving an initial headache response following treatment with zolmitriptan nasal spray is depicted in Figure 1.

Figure 1: Estimated probability of achieving an initial headache response after treatment in Study 1

Note: Figure 1 shows the Kaplan-Meier plot of the probability over time of obtaining headache response (moderate or severe headache improving to mild or no pain) following treatment with zolmitriptan nasal spray. The estimates displayed are based on a placebo controlled, outpatient trial providing evidence of efficacy. Patients not achieving headache response or taking additional treatment prior to 4 hours were censored to 4 hours.

For patients with migraine associated photophobia, phonophobia, and nausea at baseline, there was a decreased incidence of these symptoms following administration of zolmitriptan nasal spray as compared with placebo.

Four to 24 hours following the initial dose of study treatment, patients were allowed to use additional treatment for pain relief in the form of a second dose of study treatment or other medication. The estimated probability of patients taking a second dose or other medication for migraine over the 24 hours following the initial dose of study treatment is summarized in Figure 2.

Figure 2: Estimated probability of patients taking an escape medication within the 24 hours following the initial dose of study treatment in Study 1

*This Kaplan-Meier plot is based on data obtained from the placebo controlled clinical trial. Patients not using additional treatments were censored at 24 hours. The plot includes both patients who had headache response at 2 hours and those who had no response to the initial dose. It should be noted that the protocol did not allow remedication within 4 hours post dose.

The efficacy of zolmitriptan was unaffected by presence of aura; presence of headache upon awakening, relationship to menses; gender, age or weight of the patient; or presence of pre-treatment nausea.

The efficacy of zolmitriptan nasal spray 5 mg was further supported by an interim analysis of another similarly designed trial. The 2-hour headache response rates for the first 210 subjects in that study for zolmitriptan 5 mg and placebo were 70% and 47%, respectively (N=108 and 102, respectively, p=0.0006).

The efficacy of zolmitriptan nasal spray in the acute treatment of migraine headache with or without aura in pediatrics patients 12 to 17 years of age was demonstrated in Study 2, a randomized, double-blind, placebo-controlled trial with a single-blind run-in period.

Patients had to have an established diagnosis of migraine (history indicating the presence of migraine for at least 1 year) with or without aura with a typical untreated migraine headache attack lasting 3 hours or more. The study included treatment of a single migraine headache attack with 1 dose of single-blind placebo during the 30-day run-in period. If the patient met all conditions for randomization, including a lack of response to the placebo run-in, a subsequent single migraine headache attack was treated with 1 blinded dose of either zolmitriptan nasal spray 5 mg, 2.5 mg, or matching placebo.

In Study 2, of the patients taking zolmitriptan nasal spray 2.5 mg or 5 mg, 62% were female and 93% were Caucasian, with a mean age of 14 years (range 12 to 17 years).

Study 2 evaluated the proportion of pediatric patients 12 to 17 years of age who had no headache pain at 2 hours following treatment. Headache response (defined as a reduction in migraine-related headache pain severity from moderate or severe pain to mild or no pain) and the absence of nausea, photophobia, and phonophobia at 2 hours post treatment were also assessed. As shown in Table 4, the percentage of pediatric patients 12 to 17 years of age with no headache pain at 2 hours following treatment was significantly higher for zolmitriptan nasal spray 5 mg than placebo.

Table 4: Percentage of Pediatric Patients 12 to 17 Years of Age with No Headache Pain, With Headache Response, No Nausea, No Photophobia, and No Phonophobia Two Hours after Treatment in Study 2

<div class="scrollingtable"><table width="100%"> <col width="24%"/> <col width="24%"/> <col width="25%"/> <col width="25%"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Two Hours Following Treatment</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"></td><td class="Botrule Lrule Rrule Toprule" valign="top"></td><td class="Botrule Lrule Rrule Toprule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"></td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Placebo</span> </p> <p> <span class="Bold">(N=253)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Zolmitriptan</span> </p> <p> <span class="Bold">2.5 mg</span> </p> <p> <span class="Bold">(N=81)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Zolmitriptan</span> </p> <p> <span class="Bold">5 mg</span> </p> <p> <span class="Bold">(N=229)</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">No Headache Pain</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">17%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">25%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">30%*</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">With Headache Response</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">39%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">53%*</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">51%*</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">No Photophobia</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">44%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">66%*</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">56%*</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">No Phonophobia</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">48%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">61%*</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">58%*</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">No Nausea</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">66%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">70%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">72%</p> </td> </tr> </tbody> </table></div>

*p < 0.05 in comparison with placebo

Two to 24 hours following the initial dose of study treatment, patients were allowed to use their usual medication for pain relief. The estimated probability of patients taking escape medication during the first 24 hours following the initial dose of study treatment is summarized in Figure 3.

Figure 3: Estimated Probability of Pediatric Patients 12 to 17 Years of Age Taking an Escape Medication Within the 24 Hours Following the Initial Dose of Study Treatment in Study 2

The Zolmitriptan Nasal Spray device is a white plastic device, labeled to indicate the nominal dose. Each Zolmitriptan Nasal Spray device administers a single dose of zolmitriptan.

{ "type": "p", "children": [], "text": "The Zolmitriptan Nasal Spray device is a white plastic device, labeled to indicate the nominal dose. Each Zolmitriptan Nasal Spray device administers a single dose of zolmitriptan." }

Zolmitriptan Nasal Spray, USP is supplied as a clear to pale yellow solution of zolmitriptan, buffered to a pH 5.0. Each Zolmitriptan Nasal Spray device contains 5 mg of zolmitriptan in a 100 μL unit dose aqueous buffered solution containing citric acid, anhydrous, USP, disodium phosphate dodecahydrate USP, benzalkonium chloride solution NF and purified water USP.

{ "type": "p", "children": [], "text": "Zolmitriptan Nasal Spray, USP is supplied as a clear to pale yellow solution of zolmitriptan, buffered to a pH 5.0. Each Zolmitriptan Nasal Spray device contains 5 mg of zolmitriptan in a 100 μL unit dose aqueous buffered solution containing citric acid, anhydrous, USP, disodium phosphate dodecahydrate USP, benzalkonium chloride solution NF and purified water USP." }

5 mg Zolmitriptan Nasal Spray is supplied in boxes of 6 single-use nasal spray units. (NDC 72162-1425-02)

{ "type": "p", "children": [], "text": "5 mg Zolmitriptan Nasal Spray is supplied in boxes of 6 single-use nasal spray units. (NDC 72162-1425-02)" }

Each Zolmitriptan Nasal Spray single dose unit spray (NDC 72162-1425-04) supplies 5 mg of zolmitriptan. The Zolmitriptan Nasal Spray unit must be discarded after use.

{ "type": "p", "children": [], "text": "Each Zolmitriptan Nasal Spray single dose unit spray (NDC 72162-1425-04) supplies 5 mg of zolmitriptan. The Zolmitriptan Nasal Spray unit must be discarded after use." }

Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].

{ "type": "p", "children": [], "text": "Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]." }

Repackaged/Relabeled by:Bryant Ranch Prepack, Inc.Burbank, CA 91504

{ "type": "p", "children": [], "text": "Repackaged/Relabeled by:Bryant Ranch Prepack, Inc.Burbank, CA 91504" }

Advise the patient to read the FDA-approved patient labeling (Patient Information).

{ "type": "p", "children": [], "text": "Advise the patient to read the FDA-approved patient labeling (Patient Information)." }

Risk of Myocardial Ischemia and/or Infarction, Prinzmetal’s angina, Other Vasospasm-related Events, and Cerebrovascular Events

{ "type": "p", "children": [], "text": "\nRisk of Myocardial Ischemia and/or Infarction, Prinzmetal’s angina, Other Vasospasm-related Events, and Cerebrovascular Events\n" }

Inform patients that zolmitriptan may cause serious cardiovascular side effects such as myocardial infarction or stroke, which may result in hospitalization and even death. Although serious cardiovascular events can occur without warning symptoms, patients should be alert for the signs and symptoms of chest pain, shortness of breath, weakness, slurring of speech, and should ask for medical advice when observing any indicative sign or symptoms [see Warnings and Precautions (5.1, 5.2, 5.4, 5.5)].

{ "type": "p", "children": [], "text": "Inform patients that zolmitriptan may cause serious cardiovascular side effects such as myocardial infarction or stroke, which may result in hospitalization and even death. Although serious cardiovascular events can occur without warning symptoms, patients should be alert for the signs and symptoms of chest pain, shortness of breath, weakness, slurring of speech, and should ask for medical advice when observing any indicative sign or symptoms [see Warnings and Precautions (5.1, 5.2, 5.4, 5.5)]." }

Medication Overuse Headache

{ "type": "p", "children": [], "text": "\nMedication Overuse Headache\n" }

Inform patients that use of acute migraine drugs for 10 or more days per month may lead to an exacerbation of headache, and encourage patients to record headache frequency and drug use (e.g., by keeping a headache diary) [see Warnings and Precautions (5.6)].

{ "type": "p", "children": [], "text": "Inform patients that use of acute migraine drugs for 10 or more days per month may lead to an exacerbation of headache, and encourage patients to record headache frequency and drug use (e.g., by keeping a headache diary) [see Warnings and Precautions (5.6)]." }

Serotonin Syndrome

{ "type": "p", "children": [], "text": "\nSerotonin Syndrome\n" }

Inform patients about the risk of serotonin syndrome with the use of zolmitriptan or other triptans, particularly during combined use with selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs) [see Warnings and Precautions (5.7)].

{ "type": "p", "children": [], "text": "Inform patients about the risk of serotonin syndrome with the use of zolmitriptan or other triptans, particularly during combined use with selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs) [see Warnings and Precautions (5.7)]." }

Pregnancy

{ "type": "p", "children": [], "text": "\nPregnancy\n" }

Advise patients to notify their healthcare provider if they are pregnant or plan to become pregnant.

{ "type": "p", "children": [], "text": "Advise patients to notify their healthcare provider if they are pregnant or plan to become pregnant." }

Lactation

{ "type": "p", "children": [], "text": "\nLactation\n" }

Advise patients to notify their healthcare provider if they are breastfeeding or plan to breastfeed [see Use in Specific Populations (8.2)].

{ "type": "p", "children": [], "text": "Advise patients to notify their healthcare provider if they are breastfeeding or plan to breastfeed [see Use in Specific Populations (8.2)]." }

Handling of Zolmitriptan Nasal Spray device

{ "type": "p", "children": [], "text": "\nHandling of Zolmitriptan Nasal Spray device\n" }

The Zolmitriptan Nasal Spray device is a white plastic device, labeled to indicate the nominal dose. The device is packaged in individual plastic packs and supplied in boxes of 6 single-use nasal spray devices. Caution patients to not remove the device from the plastic pack prior to dosing. The Zolmitriptan Nasal Spray device is placed in a nostril and actuated to deliver a single dose. Caution patients to avoid spraying the contents of the device in their eyes.

{ "type": "p", "children": [], "text": "The Zolmitriptan Nasal Spray device is a white plastic device, labeled to indicate the nominal dose. The device is packaged in individual plastic packs and supplied in boxes of 6 single-use nasal spray devices. Caution patients to not remove the device from the plastic pack prior to dosing. The Zolmitriptan Nasal Spray device is placed in a nostril and actuated to deliver a single dose. Caution patients to avoid spraying the contents of the device in their eyes." }

Manufactured By Padagis

{ "type": "p", "children": [], "text": "Manufactured By Padagis" }

Yeruham, Israel

{ "type": "p", "children": [], "text": "Yeruham, Israel" }

Distributed By PadagisTM

{ "type": "p", "children": [], "text": "Distributed By PadagisTM\n" }

Allegan, MI 49010

{ "type": "p", "children": [], "text": "Allegan, MI 49010" }

www.padagis.com

{ "type": "p", "children": [], "text": "www.padagis.com" }

Rev 11-22

{ "type": "p", "children": [], "text": "Rev 11-22" }

Zolmitriptan (zohl-mi-TRIP-tan)

{ "type": "p", "children": [], "text": "\nZolmitriptan (zohl-mi-TRIP-tan)\n" }

Nasal Spray

{ "type": "p", "children": [], "text": "\nNasal Spray\n" }

Please read this information before you start taking Zolmitriptan Nasal Spray and each time you renew your prescription just in case anything has changed. Remember, this summary does not take the place of discussions with your doctor. You and your doctor should discuss Zolmitriptan Nasal Spray when you start taking your medication and at regular checkups.

{ "type": "p", "children": [], "text": "Please read this information before you start taking Zolmitriptan Nasal Spray and each time you renew your prescription just in case anything has changed. Remember, this summary does not take the place of discussions with your doctor. You and your doctor should discuss Zolmitriptan Nasal Spray when you start taking your medication and at regular checkups." }

What is Zolmitriptan Nasal Spray?

{ "type": "p", "children": [], "text": "\nWhat is Zolmitriptan Nasal Spray?\n" }

Zolmitriptan Nasal Spray is a prescription medicine used to treat migraine headaches with or without aura in adults and pediatric patients (12 to 17 years of age).

{ "type": "p", "children": [], "text": "Zolmitriptan Nasal Spray is a prescription medicine used to treat migraine headaches with or without aura in adults and pediatric patients (12 to 17 years of age)." }

Zolmitriptan Nasal Spray is not for other types of headaches.

{ "type": "p", "children": [], "text": "Zolmitriptan Nasal Spray is not for other types of headaches." }

Zolmitriptan Nasal Spray is not for the prevention of migraine headaches.

{ "type": "p", "children": [], "text": "Zolmitriptan Nasal Spray is not for the prevention of migraine headaches." }

It is not known if Zolmitriptan Nasal Spray is safe and effective to treat cluster headaches.

{ "type": "p", "children": [], "text": "It is not known if Zolmitriptan Nasal Spray is safe and effective to treat cluster headaches." }

Zolmitriptan Nasal Spray is not for people with moderate or severe liver problems (hepatic impairment).

{ "type": "p", "children": [], "text": "Zolmitriptan Nasal Spray is not for people with moderate or severe liver problems (hepatic impairment)." }

It is not known if Zolmitriptan Nasal Spray is safe and effective in children under 12 years of age.

{ "type": "p", "children": [], "text": "It is not known if Zolmitriptan Nasal Spray is safe and effective in children under 12 years of age." }

Who should not use Zolmitriptan Nasal Spray?

{ "type": "p", "children": [], "text": "\nWho should not use Zolmitriptan Nasal Spray?\n" }

Do not use Zolmitriptan Nasal Spray if you have:

{ "type": "p", "children": [], "text": "\nDo not use Zolmitriptan Nasal Spray if you have:\n" }

{ "type": "", "children": [], "text": "" }

What should I tell my doctor before using Zolmitriptan Nasal Spray?

{ "type": "p", "children": [], "text": "\nWhat should I tell my doctor before using Zolmitriptan Nasal Spray?\n" }

Before using Zolmitriptan Nasal Spray, tell your doctor about all of your medical conditions, including if you:

{ "type": "p", "children": [], "text": "\nBefore using Zolmitriptan Nasal Spray, tell your doctor about all of your medical conditions, including if you:\n" }

{ "type": "", "children": [], "text": "" }

Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

{ "type": "p", "children": [], "text": "\nTell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements." }

Especially tell your doctor if you take:

{ "type": "p", "children": [], "text": "Especially tell your doctor if you take:" }

{ "type": "", "children": [], "text": "" }

How should I use Zolmitriptan Nasal Spray?

{ "type": "p", "children": [], "text": "\nHow should I use Zolmitriptan Nasal Spray?\n" }

For detailed instructions, see the step-by-step instructions for using Zolmitriptan Nasal Spray at the end of this Patient Information.

{ "type": "p", "children": [], "text": "\nFor detailed instructions, see the step-by-step instructions for using Zolmitriptan Nasal Spray at the end of this Patient Information.\n" }

{ "type": "", "children": [], "text": "" }

What should I avoid while using Zolmitriptan Nasal Spray?

{ "type": "p", "children": [], "text": "\nWhat should I avoid while using Zolmitriptan Nasal Spray?\n" }

Zolmitriptan Nasal Spray can cause dizziness, weakness, or drowsiness. If you have these symptoms do not drive a car, use machinery, or do anything that needs you to be alert.

{ "type": "p", "children": [], "text": "Zolmitriptan Nasal Spray can cause dizziness, weakness, or drowsiness. If you have these symptoms do not drive a car, use machinery, or do anything that needs you to be alert." }

What are the possible side effects of Zolmitriptan Nasal Spray?

{ "type": "p", "children": [], "text": "\nWhat are the possible side effects of Zolmitriptan Nasal Spray?\n" }

Zolmitriptan Nasal Spray can cause serious side effects.

{ "type": "p", "children": [], "text": "\nZolmitriptan Nasal Spray can cause serious side effects.\n" }

Call your doctor right away if you have any of the following symptoms after using Zolmitriptan Nasal Spray:

{ "type": "p", "children": [], "text": "\nCall your doctor right away if you have any of the following symptoms after using Zolmitriptan Nasal Spray:\n" }

{ "type": "", "children": [], "text": "" }

The most common side effects of Zolmitriptan Nasal Spray are:

{ "type": "p", "children": [], "text": "The most common side effects of Zolmitriptan Nasal Spray are:" }

{ "type": "", "children": [], "text": "" }

These are not all the possible side effects of Zolmitriptan Nasal Spray. For more information ask your doctor or pharmacist.

{ "type": "p", "children": [], "text": "These are not all the possible side effects of Zolmitriptan Nasal Spray. For more information ask your doctor or pharmacist." }

Call your doctor for medical advice about side effects.

{ "type": "p", "children": [], "text": "Call your doctor for medical advice about side effects." }

You may report side effects to FDA at 1-800-FDA-1088.

{ "type": "p", "children": [], "text": "You may report side effects to FDA at 1-800-FDA-1088." }

How should I store Zolmitriptan Nasal Spray?

{ "type": "p", "children": [], "text": "\nHow should I store Zolmitriptan Nasal Spray?\n" }

Store Zolmitriptan Nasal Spray at room temperature between 68°F to 77°F (20°C -25°C).

{ "type": "p", "children": [], "text": "Store Zolmitriptan Nasal Spray at room temperature between 68°F to 77°F (20°C -25°C)." }

Keep Zolmitriptan Nasal Spray and all medicines out of the reach of children.

{ "type": "p", "children": [], "text": "\nKeep Zolmitriptan Nasal Spray and all medicines out of the reach of children.\n" }

General information about the safe and effective use of Zolmitriptan Nasal Spray.

{ "type": "p", "children": [], "text": "\nGeneral information about the safe and effective use of Zolmitriptan Nasal Spray.\n" }

Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflets. Do not use Zolmitriptan Nasal Spray for a condition for which it was not prescribed. Do not give Zolmitriptan Nasal Spray to other people, even if they have the same symptoms that you have. It may harm them.

{ "type": "p", "children": [], "text": "Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflets. Do not use Zolmitriptan Nasal Spray for a condition for which it was not prescribed. Do not give Zolmitriptan Nasal Spray to other people, even if they have the same symptoms that you have. It may harm them." }

This leaflet summarizes the most important information about Zolmitriptan Nasal Spray. If you would like more information, talk to your doctor. You can ask your pharmacist or doctor for information about Zolmitriptan Nasal Spray that is written for health professionals.

{ "type": "p", "children": [], "text": "This leaflet summarizes the most important information about Zolmitriptan Nasal Spray. If you would like more information, talk to your doctor. You can ask your pharmacist or doctor for information about Zolmitriptan Nasal Spray that is written for health professionals." }

For more information go to www.padagis.com or call 1-866-634-9120.

{ "type": "p", "children": [], "text": "For more information go to www.padagis.com or call 1-866-634-9120." }

What are the Ingredients in Zolmitriptan Nasal Spray?

{ "type": "p", "children": [], "text": "\nWhat are the Ingredients in Zolmitriptan Nasal Spray?\n" }

Active ingredient: zolmitriptan

{ "type": "p", "children": [], "text": "\nActive ingredient: zolmitriptan" }

Inactive ingredients: anhydrous citric acid, dibasic sodium phosphate, benzalkonium chloride solution and purified water

{ "type": "p", "children": [], "text": "\nInactive ingredients: anhydrous citric acid, dibasic sodium phosphate, benzalkonium chloride solution and purified water" }

The brands listed are the registered trademarks of their respective owners.

{ "type": "p", "children": [], "text": "The brands listed are the registered trademarks of their respective owners." }

Manufactured By Padagis

{ "type": "p", "children": [], "text": "Manufactured By Padagis" }

Yeruham, Israel

{ "type": "p", "children": [], "text": "Yeruham, Israel" }

Distributed By Padagis

{ "type": "p", "children": [], "text": "Distributed By Padagis" }

Allegan, MI 49010

{ "type": "p", "children": [], "text": "Allegan, MI 49010" }

www.padagis.com

{ "type": "p", "children": [], "text": "www.padagis.com" }

Rev 11-22

{ "type": "p", "children": [], "text": "Rev 11-22" }

Zolmitriptan (zohl-mi-TRIP-tan)

{ "type": "p", "children": [], "text": "\nZolmitriptan (zohl-mi-TRIP-tan)\n" }

Nasal Spray

{ "type": "p", "children": [], "text": "\nNasal Spray\n" }

Important: For use in your nose only. Do not spray in your eyes.

{ "type": "p", "children": [], "text": "\nImportant: For use in your nose only. Do not spray in your eyes.\n" }

Note: There is only 1 dose in the nasal sprayer. Do not try to prime the nasal sprayer or you will lose the dose. Do not press the plunger until you have put the tip into your nostril or you will lose the dose.

{ "type": "p", "children": [], "text": "\nNote: There is only 1 dose in the nasal sprayer. Do not try to prime the nasal sprayer or you will lose the dose. Do not press the plunger until you have put the tip into your nostril or you will lose the dose.\n" }

Steps for using Zolmitriptan Nasal Spray

{ "type": "p", "children": [], "text": "\nSteps for using Zolmitriptan Nasal Spray\n" }

{ "type": "", "children": [], "text": "" }

{ "type": "", "children": [], "text": "" }

{ "type": "", "children": [], "text": "" }

Insert the tip of the sprayer device into your open nostril as far as feels comfortable and tilt your head slightly (See Figure D).

{ "type": "p", "children": [], "text": "Insert the tip of the sprayer device into your open nostril as far as feels comfortable and tilt your head slightly (See Figure D).\n" }

Do not press the plunger yet.

{ "type": "p", "children": [], "text": "\nDo not press the plunger yet.\n" }

{ "type": "", "children": [], "text": "" }

The plunger may feel stiff and you may hear a click. Keep your head slightly tilted back and remove the tip from your nose. Breathe gently through your mouth for 5 to 10 seconds. You may feel liquid in your nose or the back of your throat. This is normal.

{ "type": "p", "children": [], "text": "The plunger may feel stiff and you may hear a click. Keep your head slightly tilted back and remove the tip from your nose. Breathe gently through your mouth for 5 to 10 seconds. You may feel liquid in your nose or the back of your throat. This is normal." }

{ "type": "", "children": [], "text": "" }

This Patient Information and Instructions for Use have been approved by the U.S. Food and Drug Administration.

{ "type": "p", "children": [], "text": "This Patient Information and Instructions for Use have been approved by the U.S. Food and Drug Administration." }

Manufactured By Padagis

{ "type": "p", "children": [], "text": "Manufactured By Padagis" }

Yeruham, Israel

{ "type": "p", "children": [], "text": "Yeruham, Israel" }

Distributed By

{ "type": "p", "children": [], "text": "Distributed By" }

PadagisTM

{ "type": "p", "children": [], "text": "PadagisTM\n" }

Allegan, MI 49010 • www.padagis.com

{ "type": "p", "children": [], "text": "Allegan, MI 49010 • www.padagis.com" }

Rev 11-22

{ "type": "p", "children": [], "text": "Rev 11-22" }

6R600 RC J5

{ "type": "p", "children": [], "text": "6R600 RC J5" }

Zolmitriptan Nasal Spray 5 mg #6

{ "type": "p", "children": [], "text": "Zolmitriptan Nasal Spray 5 mg #6" }

Zolmitriptan tablets are indicated for the acute treatment of migraine with or without aura in adults.

{ "type": "p", "children": [], "text": "Zolmitriptan tablets are indicated for the acute treatment of migraine with or without aura in adults." }

Limitations of Use:

{ "type": "p", "children": [], "text": "\nLimitations of Use:\n" }

{ "type": "ul", "children": [ "Only use zolmitriptan tablets if a clear diagnosis of migraine has been established. If a patient has no response to zolmitriptan tablets treatment for the first migraine attack, reconsider the diagnosis of migraine before zolmitriptan tablets are administered to treat any subsequent attacks.", "Zolmitriptan tablets are not indicated for the prevention of migraine attacks.", "Safety and effectiveness of zolmitriptan tablets have not been established for cluster headache." ], "text": "" }

The recommended starting dose of zolmitriptan tablets is 1.25 mg or 2.5 mg. The 1.25 mg dose can be achieved by manually breaking the functionally-scored 2.5 mg tablet in half. The maximum recommended single dose of zolmitriptan tablets is 5 mg. In controlled clinical trials, a greater proportion of patients had headache response following a 2.5 mg or 5 mg dose than following a 1 mg dose. There was little added benefit from the 5 mg dose compared to the 2.5 mg dose, but adverse reactions were more frequent with the 5 mg dose.

If the migraine has not resolved by 2 hours after taking zolmitriptan tablets, or returns after a transient improvement, a second dose may be administered at least 2 hours after the first dose. The maximum daily dose is 10 mg in any 24-hour period.

The safety of zolmitriptan tablets in the treatment of an average of more than three migraines in a 30-day period has not been established.

The recommended dose of zolmitriptan tablets in patients with moderate to severe hepatic impairment is 1.25 mg (one-half of one 2.5 mg zolmitriptan tablets) because of increased zolmitriptan blood levels in these patients and elevation of blood pressure in some of these patients. Limit the total daily dose in patients with severe hepatic impairment to no more than 5 mg per day.

If zolmitriptan tablets  is co-administered with cimetidine, limit the maximum single dose of zolmitriptan tablets  to 2.5 mg, not to exceed 5 mg in any 24-hour period [see Drug Interactions (7.5), Clinical Pharmacology (12.3)].

2.5 mg Tablets:Pink, round, biconvex, film-coated tablets with "ZL 1" engraved on one side and break line on other side (functionally-scored).

{ "type": "p", "children": [], "text": "\n2.5 mg Tablets:Pink, round, biconvex, film-coated tablets with \"ZL 1\" engraved on one side and break line on other side (functionally-scored).\n\n " }

5 mg Tablets:Yellow, round, biconvex, film-coated tablets with "ZL 2" engraved on one side and plain on other side (not scored).

{ "type": "p", "children": [], "text": "\n5 mg Tablets:Yellow, round, biconvex, film-coated tablets with \"ZL 2\" engraved on one side and plain on other side (not scored).\n\n " }

Zolmitriptan tablets are contraindicated in patients with:

{ "type": "p", "children": [], "text": "Zolmitriptan tablets are contraindicated in patients with:" }

{ "type": "ul", "children": [ "Ischemic coronary artery disease (angina pectoris, history of myocardial infarction, or documented silent ischemia), other significant underlying cardiovascular disease, or coronary artery vasospasm including Prinzmetal’s angina\n \n [seeWarnings and Precautions (5.1)].\n \n ", "Wolff-Parkinson-White syndrome or arrhythmias associated with other cardiac accessory  conduction pathway disorders\n \n [seeWarnings and Precautions (5.2)].\n \n ", "History of stroke, transient ischemic attack (TIA), or history of hemiplegic or basilar  migraine because these patients are at a higher risk of stroke\n \n [seeWarnings and Precautions (5.4)].\n \n ", "Peripheral vascular disease (PVD)\n \n [seeWarnings and Precautions (5.5)].\n \n ", "Ischemic bowel disease\n \n [seeWarnings and Precautions (5.5)].\n \n ", "Uncontrolled hypertension\n \n [seeWarnings and Precautions (5.8)].\n \n ", "Recent use (i.e., within 24 hours) of another 5-HT\n \n 1agonist, ergotamine-containing medication, or ergot-type medication (such as dihydroergotamine or methysergide)\n \n [seeDrug Interactions (7.1,7.3)] .\n", "Concurrent administration of a monoamine oxidase (MAO)-A inhibitor or recent use of a MAO-A inhibitor (that is within 2 weeks)\n \n [seeDrug Interactions (7.2),\n \n Clinical Pharmacology (12.3)].\n \n ", "Known hypersensitivity to zolmitriptan (angioedema and anaphylaxis seen)\n \n [seeAdverse Reactions (6.2)].\n" ], "text": "" }

Zolmitriptan tablets are contraindicated in patients with ischemic or vasospastic coronary artery disease (CAD). There have been rare reports of serious cardiac adverse reactions, including acute myocardial infarction, occurring within a few hours following administration of zolmitriptan tablets. Some of these reactions occurred in patients without known CAD. 5-HT 1agonists including zolmitriptan tablets may cause coronary artery vasospasm (Prinzmetal's Angina), even in patients without a history of CAD.

Perform a cardiovascular evaluation in triptan-naïve patients who have multiple cardiovascular risk factors (e.g., increased age, diabetes, hypertension, smoking, obesity, strong family history of CAD) prior to receiving zolmitriptan tablets. Do not administer zolmitriptan tablets if there is evidence of CAD or coronary artery vasospasm [seeContraindications (4)]. For patients with multiple cardiovascular risk factors who have a negative cardiovascular evaluation, consider administering the first zolmitriptan tablets dose in a medically-supervised setting and performing an electrocardiogram (ECG) immediately following zolmitriptan tablets administration. For such patients, consider periodic cardiovascular evaluation in intermittent long-term users of zolmitriptan tablets.

Life-threatening disturbances of cardiac rhythm including ventricular tachycardia and ventricular fibrillation leading to death have been reported within a few hours following the administration of 5-HT 1agonists. Discontinue zolmitriptan tablets if these disturbances occur. Zolmitriptan tablets are contraindicated in patients with Wolff-Parkinson-White syndrome or arrhythmias associated with other cardiac accessory conduction pathway disorders [seeContraindications (4)].

As with other 5-HT 1agonists, sensations of tightness, pain, and pressure in the chest, throat, neck, and jaw commonly occur after treatment with zolmitriptan tablets and is usually non-cardiac in origin. However, perform a cardiac evaluation if these patients are at high cardiac risk. 5-HT 1agonists including zolmitriptan tablets are contraindicated in patients with CAD or Prinzmetal’s variant angina [seeContraindications (4)].

Cerebral hemorrhage, subarachnoid hemorrhage, and stroke have occurred in patients treated with 5-HT 1agonists, and some have resulted in fatalities. In a number of cases, it appears possible that the cerebrovascular events were primary, the 5-HT 1agonist having been administered in the incorrect belief that the symptoms experienced were a consequence of migraine, when they were not.

As with other acute migraine therapies, before treating headaches in patients not previously diagnosed as migraineurs, and in migraineurs who present with symptoms atypical for migraine, exclude other potentially serious neurological conditions. Zolmitriptan tablets are contraindicated in patients with a history of stroke or transient ischemic attack [seeContraindications (4)].

5-HT 1agonists, including zolmitriptan tablets, may cause non-coronary vasospastic reactions, such as peripheral vascular ischemia, gastrointestinal vascular ischemia and infarction (presenting with abdominal pain and bloody diarrhea), splenic infarction, and Raynaud’s syndrome. In patients who experience symptoms or signs suggestive of a vasospastic reaction following the use of any 5-HT 1agonist, rule out a vasospastic reaction before receiving additional zolmitriptan tablets doses [seeContraindications (4)].

Reports of transient and permanent blindness and significant partial vision loss have been reported with the use of 5-HT 1agonists. Since visual disorders may be part of a migraine attack, a causal relationship between these events and the use of 5-HT 1agonists has not been clearly established.

Overuse of acute migraine drugs (e.g., ergotamine, triptans, opioids, or a combination of drugs for 10 or more days per month) may lead to exacerbation of headache (medication overuse headache). Medication overuse headache may present as migraine-like daily headaches or as a marked increase in frequency of migraine attacks. Detoxification of patients, including withdrawal of the overused drugs, and treatment of withdrawal symptoms (which often includes a transient worsening of headache) may be necessary.

Serotonin syndrome may occur with triptans, including zolmitriptan tablets , particularly during co-administration with selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), and MAO inhibitors [ see Drug Interactions (7.5)]. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). The onset of symptoms usually rapidly occurs within minutes to hours of receiving a new or a greater dose of a serotonergic medication. Discontinue zolmitriptan tablets if serotonin syndrome is suspected [seeDrug Interactions (7.4)].

Significant elevations in systemic blood pressure have been reported in patients treated with 5-HT 1agonists including patients without a history of hypertension; very rarely, these increases in blood pressure have been associated with serious adverse reactions. In healthy subjects treated with 5 mg of zolmitriptan tablets, an increase of 1 and 5 mm Hg in the systolic and diastolic blood pressure, respectively, was seen. In a study of patients with moderate to severe liver impairment, 7 of 27 patients experienced 20 to 80 mm Hg elevations in systolic and/or diastolic blood pressure after a dose of 10 mg of zolmitriptan tablets.

As with all triptans, blood pressure should be monitored in zolmitriptan tablets-treated patients. Zolmitriptan tablets are contraindicated in patients with uncontrolled hypertension [seeContraindications (4)].

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.

In a long-term, open-label study where patients were allowed to treat multiple migraine attacks for up to 1 year, 8% (167 out of 2,058) withdrew from the trial because of adverse reaction.

The most common adverse reactions (≥5% and > placebo) in these trials were neck/throat/jaw pain, dizziness, paresthesia, asthenia, somnolence, warm/cold sensation, nausea, heaviness sensation, and dry mouth.

Table 1 lists the adverse reactions that occurred in ≥2% of the 2,074 patients in any one of the zolmitriptan tablets 1 mg, 2.5 mg, or 5 mg dose groups in the controlled clinical trials of zolmitriptan tablets  in patients with migraines (Studies 1, 2, 3, 4, and 5) [see Clinical Studies ( 14)] . Only adverse reactions that were at least 2% more frequent in a zolmitriptan tablets group compared to the placebo group are included.

Several of the adverse reactions appear dose related, notably paresthesia, sensation of heaviness or tightness in chest, neck, jaw, and throat, dizziness, somnolence and possibly asthenia and nausea.

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="100%"> <caption> <span>Table 1: Adverse Reaction Incidence in Five Pooled Placebo-Controlled Migraine Clinical Trials*</span> </caption> <col width="32.84%"/> <col width="13.32%"/> <col width="16.42%"/> <col width="15.38%"/> <col width="22.04%"/> <tfoot> <tr class="First Last"> <td colspan="105"><span class="Sup">*</span>Only adverse reactions that were at least 2% more frequent in a zolmitriptan tablets group compared to the placebo group are included. </td> </tr> </tfoot> <tbody class="Headless"> <tr class="Botrule First"> <td align="justify" class="Lrule Rrule" valign="top"> <br/> </td><td align="center" class="Rrule" valign="middle">Placebo <br/> (n=401) <br/> </td><td align="center" class="Rrule" valign="middle">Zolmitriptan tablets <br/> 1 mg <br/> (n=163) <br/> </td><td align="center" class="Rrule" valign="middle">Zolmitriptan tablets <br/> 2.5 mg <br/> (n=498) <br/> </td><td align="center" class="Rrule" valign="middle">Zolmitriptan tablets <br/> 5 mg <br/> (n=1012) <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="middle"><span class="Bold">ATYPICAL SENSATIONS</span> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">6%</span> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">12%</span> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">12%</span> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">18%</span> <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="middle">Paresthesia (all types) <br/> </td><td align="center" class="Rrule" valign="middle">2% <br/> </td><td align="center" class="Rrule" valign="middle">5% <br/> </td><td align="center" class="Rrule" valign="middle">7% <br/> </td><td align="center" class="Rrule" valign="middle">9% <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="middle">Warm/cold sensation <br/> </td><td align="center" class="Rrule" valign="middle">4% <br/> </td><td align="center" class="Rrule" valign="middle">6% <br/> </td><td align="center" class="Rrule" valign="middle">5% <br/> </td><td align="center" class="Rrule" valign="middle">7% <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="middle"><span class="Bold">PAIN AND PRESSURE SENSATIONS</span> <br/> </td><td align="center" class="Rrule" valign="top"><span class="Bold">7%</span> <br/> </td><td align="center" class="Rrule" valign="top"><span class="Bold">13%</span> <br/> </td><td align="center" class="Rrule" valign="top"><span class="Bold">14%</span> <br/> </td><td align="center" class="Rrule" valign="top"><span class="Bold">22%</span> <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="middle">Chest- <br/> pain/tightness/pressure and/or heaviness <br/> </td><td align="center" class="Rrule" valign="middle">1% <br/> </td><td align="center" class="Rrule" valign="middle">2% <br/> </td><td align="center" class="Rrule" valign="middle">3% <br/> </td><td align="center" class="Rrule" valign="middle">4% <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">Neck/throat/jaw - pain/tightness/pressure <br/> </td><td align="center" class="Rrule" valign="top">3% <br/> </td><td align="center" class="Rrule" valign="top">4% <br/> </td><td align="center" class="Rrule" valign="top">7% <br/> </td><td align="center" class="Rrule" valign="top">10% <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="middle">Heaviness other than chest or neck <br/> </td><td align="center" class="Rrule" valign="top">1% <br/> </td><td align="center" class="Rrule" valign="top">1% <br/> </td><td align="center" class="Rrule" valign="top">2% <br/> </td><td align="center" class="Rrule" valign="top">5% <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="bottom">Other- Pressure/tightness/heaviness <br/> </td><td align="center" class="Rrule" valign="top">0% <br/> </td><td align="center" class="Rrule" valign="top">2% <br/> </td><td align="center" class="Rrule" valign="top">2% <br/> </td><td align="center" class="Rrule" valign="top">2% <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="middle"><span class="Bold">DIGESTIVE</span> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">8%</span> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">11%</span> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">16%</span> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">14%</span> <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="middle">Dry mouth <br/> </td><td align="center" class="Rrule" valign="middle">2% <br/> </td><td align="center" class="Rrule" valign="middle">5% <br/> </td><td align="center" class="Rrule" valign="middle">3% <br/> </td><td align="center" class="Rrule" valign="middle">3% <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Dyspepsia <br/> </td><td align="center" class="Rrule" valign="middle">1% <br/> </td><td align="center" class="Rrule" valign="middle">3% <br/> </td><td align="center" class="Rrule" valign="middle">2% <br/> </td><td align="center" class="Rrule" valign="middle">1% <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="middle">Dysphagia <br/> </td><td align="center" class="Rrule" valign="middle">0% <br/> </td><td align="center" class="Rrule" valign="middle">0% <br/> </td><td align="center" class="Rrule" valign="middle">0% <br/> </td><td align="center" class="Rrule" valign="middle">2% <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="middle">Nausea <br/> </td><td align="center" class="Rrule" valign="middle">4% <br/> </td><td align="center" class="Rrule" valign="middle">4% <br/> </td><td align="center" class="Rrule" valign="middle">9% <br/> </td><td align="center" class="Rrule" valign="middle">6% <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="middle"><span class="Bold">NEUROLOGICAL</span> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">10%</span> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">11%</span> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">17%</span> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">21%</span> <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="middle">Dizziness <br/> </td><td align="center" class="Rrule" valign="middle">4% <br/> </td><td align="center" class="Rrule" valign="middle">6% <br/> </td><td align="center" class="Rrule" valign="middle">8% <br/> </td><td align="center" class="Rrule" valign="middle">10% <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="middle">Somnolence <br/> </td><td align="center" class="Rrule" valign="middle">3% <br/> </td><td align="center" class="Rrule" valign="middle">5% <br/> </td><td align="center" class="Rrule" valign="middle">6% <br/> </td><td align="center" class="Rrule" valign="middle">8% <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Vertigo <br/> </td><td align="center" class="Rrule" valign="top">0% <br/> </td><td align="center" class="Rrule" valign="top">0% <br/> </td><td align="center" class="Rrule" valign="top">0% <br/> </td><td align="center" class="Rrule" valign="top">2% <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"><span class="Bold">OTHER</span> <br/> </td><td align="center" class="Rrule" valign="top"> <br/> </td><td align="center" class="Rrule" valign="top"> <br/> </td><td align="center" class="Rrule" valign="top"> <br/> </td><td align="center" class="Rrule" valign="top"> <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="middle">Asthenia <br/> </td><td align="center" class="Rrule" valign="middle">3% <br/> </td><td align="center" class="Rrule" valign="middle">5% <br/> </td><td align="center" class="Rrule" valign="middle">3% <br/> </td><td align="center" class="Rrule" valign="middle">9% <br/> </td> </tr> <tr class="Last"> <td align="justify" class="Lrule Rrule" valign="middle">Sweating <br/> </td><td align="center" class="Rrule" valign="middle">1% <br/> </td><td align="center" class="Rrule" valign="middle">0% <br/> </td><td align="center" class="Rrule" valign="middle">2% <br/> </td><td align="center" class="Rrule" valign="middle">3% <br/> </td> </tr> </tbody> </table></div>

There were no differences in the incidence of adverse reactions in controlled clinical trials in the following subgroups: gender, weight, age, use of prophylactic medications, or presence of aura. There were insufficient data to assess the impact of race on the incidence of adverse reactions.

Less Common Adverse Reactions withzolmitriptan tablets:

In the paragraphs that follow, the frequencies of less commonly reported adverse clinical reactions are presented. Because the reports include reactions observed in open and uncontrolled studies, the role of zolmitriptan tablets in their causation cannot be reliably determined. Furthermore, variability associated with adverse reaction reporting, the terminology used to describe adverse reactions, etc., limit the value of the quantitative frequency estimates provided. Adverse reaction frequencies were calculated as the number of patients who used zolmitriptan tablets  and reported a reaction divided by the total number of patients exposed to zolmitriptan tablets  (n=4,027). Reactions were further classified within body system categories and enumerated in order of decreasing frequency using the following definitions: infrequent adverse reactions (those occurring in 1/100 to 1/1,000 patients) and rare adverse reactions (those occurring in less than 1/1,000 patients).

General:Infrequent were allergic reactions.

Cardiovascular:Infrequent were arrhythmias, hypertension, and syncope. Rare was tachycardia.

Neurological:Infrequent were agitation, anxiety, depression, emotional lability and insomnia; Rare were amnesia, hallucinations, and cerebral ischemia.

Skin:Infrequent were pruritus, rash and urticaria.

Urogenital:Infrequent were polyuria, urinary frequency and urinary urgency.

Adverse Reactions with zolmitriptan orally disintegrating tablets:

The adverse reaction profile seen with zolmitriptan orally disintegrating tablets was similar to that seen with zolmitriptan tablets.

The following adverse reactions were identified during post approval use of zolmitriptan tablets. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

The reactions enumerated include all except those already listed in the Clinical Trials Experience section above or the Warnings and Precautions section.

Hypersensitivity Reactions:

As with other 5-HT 1B/1Dagonists, there have been reports of anaphylaxis, anaphylactoid, and hypersensitivity reactions including angioedema in patients receiving zolmitriptan tablets. Zolmitriptan tablets are contraindicated in patients with a history of hypersensitivity reaction to zolmitriptan tablets.

Ergot-containing drugs have been reported to cause prolonged vasospastic reactions. Because these effects may be additive, use of ergotamine containing or ergot-type medications (like dihydroergotamine or methysergide) and zolmitriptan tablets within 24 hours of each other is contraindicated [seeContraindications (4)].

MAO-A inhibitors increase the systemic exposure of zolmitriptan and its active N-desmethyl metabolite. Therefore, the use of zolmitriptan tablets in patients receiving MAO-A inhibitors is contraindicated [seeContraindications (4), Clinical Pharmacology (12.3)].

Concomitant use of other 5-HT 1B/1Dagonists (including triptans) within 24 hours of zolmitriptan tablets treatment is contraindicated because the risk of vasospastic reactions may be additive [seeContraindications (4)].

Cases of life-threatening serotonin syndrome have been reported during co-administration of triptans and selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs) [seeWarnings and Precautions (5.7)].

Following administration of cimetidine, the half-life and blood levels of zolmitriptan and its active N-desmethyl metabolite were approximately doubled [seeClinical Pharmacology (12.3)]. If cimetidine and zolmitriptan tablets are used concomitantly, limit the maximum single dose of zolmitriptan tablets to 2.5 mg, not to exceed 5 mg in any 24-hour period [seeDosage and Administration (2.4), Clinical Pharmacology (12.3)].

Risk Summary

There are no adequate data on the developmental risk associated with the use of zolmitriptan tablets in pregnant women. In reproductive toxicity studies in rats and rabbits, oral administration of zolmitriptan to pregnant animals resulted in embryolethality and fetal abnormalities (malformations and variations) at clinically relevant exposures (see Data).

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. The estimated rates of major birth defects (2.2%-2.9%) and miscarriage (17%) among deliveries to women with migraine are similar to rates reported in women without migraine.

Clinical Considerations

Disease-Associated Maternal and/or Embryo/Fetal Risk

Published data have suggested that women with migraine may be at increased risk of preeclampsia during pregnancy.

Data

Animal Data

When zolmitriptan was administered to pregnant rats during the period of organogenesis at oral doses of 100, 400, and 1200 mg/kg/day (plasma exposures (AUCs) ≈280, 1100, and 5000 times the human AUC at the maximum recommended human dose (MRHD) of 10 mg/day), there was a dose-related increase in embryolethality. A no-effect dose for embryolethality was not established. When zolmitriptan was administered to pregnant rabbits during the period of organogenesis at oral doses of 3, 10, and 30 mg/kg/day (plasma AUCs ≈1, 11, and 42 times the human AUC at the MRHD), there were increases in embryolethality and in fetal malformations and variations. The no-effect dose for adverse effects on embryofetal development was associated with plasma AUC similar to that in humans at the MRHD. When female rats were given zolmitriptan during gestation, parturition, and lactation at oral doses of 25, 100, and 400 mg/kg/day (plasma AUCs ≈70, 280, and 1100 times that in human at the MRHD), an increased incidence of hydronephrosis was found in the offspring. The no-effect dose was associated with a plasma AUC ≈280 times that in humans at the MRHD.

Risk Summary

There are no data on the presence of zolmitriptan or its metabolites in human milk, the effects on the breastfed infant, or the effects of zolmitriptan and its metabolites on milk production. In rats, oral dosing with zolmitriptan resulted in levels in milk up to 4 times that in maternal plasma.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for zolmitriptan tablets and any potential adverse effects on the breastfed infant from zolmitriptan or from the underlying maternal condition.

The safety and effectiveness in pediatric patients have not been established. Therefore, zolmitriptan tablets are not recommended for use in patients under 18 years of age.

One randomized, placebo-controlled clinical trial of zolmitriptan tablets (2.5, 5 and 10 mg) evaluated 696 pediatric patients (aged 12-17 years) with migraines. This study did not demonstrate the efficacy of zolmitriptan tablets compared to placebo in the treatment of migraine in adolescents. Adverse reactions in the adolescent patients treated with zolmitriptan tablets were similar in nature and frequency to those reported in clinical trials in adults treated with zolmitriptan tablets. Zolmitriptan tablets have not been studied in pediatric patients less than 12 years old.

In the postmarketing experience with triptans, including zolmitriptan tablets, there were no additional adverse reactions seen in pediatric patients that were not seen in adults.

Clinical studies of zolmitriptan tablets did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

A cardiovascular evaluation is recommended for geriatric patients who have other cardiovascular risk factors (e.g., diabetes, hypertension, smoking, obesity, strong family history of coronary artery disease) prior to receiving zolmitriptan tablets [seeWarnings and Precautions (5.1)].

The pharmacokinetics of zolmitriptan were similar in geriatric patients (aged > 65 years) compared to younger patients [seeClinical Pharmacology (12.3)].

After oral zolmitriptan tablets administration, zolmitriptan blood levels were increased in patients with moderate to severe hepatic impairment, and significant elevation in blood pressure was observed in some of these patients [seeWarnings and Precautions (5.8)]. Therefore, adjust the zolmitriptan tablets dose and administer with caution in patients with moderate or severe hepatic impairment [seeDosage and Administration (2.3), Clinical Pharmacology (12)].

There is no experience with acute overdose of zolmitriptan tablets. Clinical study subjects who received single 50 mg oral doses of zolmitriptan tablets commonly experienced sedation.

{ "type": "p", "children": [], "text": "There is no experience with acute overdose of zolmitriptan tablets. Clinical study subjects who received single 50 mg oral doses of zolmitriptan tablets commonly experienced sedation." }

There is no specific antidote to zolmitriptan tablets. In cases of severe intoxication, intensive care procedures are recommended, including establishing and maintaining a patent airway, ensuring adequate oxygenation and ventilation, and monitoring and support of the cardiovascular system.

{ "type": "p", "children": [], "text": "There is no specific antidote to zolmitriptan tablets. In cases of severe intoxication, intensive care procedures are recommended, including establishing and maintaining a patent airway, ensuring adequate oxygenation and ventilation, and monitoring and support of the cardiovascular system." }

The elimination half-life of zolmitriptan tablets is 3 hours [seeClinical Pharmacology (12.1)]; therefore, monitor patients after overdose with zolmitriptan tablets for at least 15 hours or until symptoms or signs resolve. It is unknown what effect hemodialysis or peritoneal dialysis has on the plasma concentrations of zolmitriptan.

{ "type": "p", "children": [], "text": "The elimination half-life of zolmitriptan tablets is 3 hours\n \n [seeClinical Pharmacology (12.1)]; therefore, monitor patients after overdose with zolmitriptan tablets for at least 15 hours or until symptoms or signs resolve. It is unknown what effect hemodialysis or peritoneal dialysis has on the plasma concentrations of zolmitriptan.\n\n " }

Zolmitriptan tablets, USP contain zolmitriptan USP, which is a selective 5-hydroxytryptamine 1B/1D(5-HT 1B/1D) receptor agonist. Zolmitriptan is chemically designated as (S)-4-[[3-[2-(dimethylamino)ethyl]-1H-indol-5-yl]methyl]-2-oxazolidinone and has the following chemical structure:

{ "type": "p", "children": [], "text": "Zolmitriptan tablets, USP contain zolmitriptan USP, which is a selective 5-hydroxytryptamine\n \n 1B/1D(5-HT\n \n 1B/1D) receptor agonist. Zolmitriptan is chemically designated as (S)-4-[[3-[2-(dimethylamino)ethyl]-1H-indol-5-yl]methyl]-2-oxazolidinone and has the following chemical structure:\n\n " }

The molecular formula is C 16H 21N 3O 2, representing a molecular weight of 287.36. Zolmitriptan is a white to cream powder that is slightly soluble in water.

{ "type": "p", "children": [], "text": "The molecular formula is C\n \n 16H\n \n 21N\n \n 3O\n \n 2, representing a molecular weight of 287.36. Zolmitriptan is a white to cream powder that is slightly soluble in water.\n\n " }

Zolmitriptan tablets, USP are available as 2.5 mg (pink) and 5 mg (yellow) film-coated tablets for oral administration. The film-coated tablets contain lactose monohydrate, microcrystalline cellulose, sodium starch glycolate, magnesium stearate, hypromellose, titanium dioxide, polyethylene glycol, ferric oxide yellow (2.5 mg and 5 mg tablet), ferric oxide red (2.5 mg tablet). Zolmitriptan tablets meets USP Dissolution Test 2.

{ "type": "p", "children": [], "text": "Zolmitriptan tablets, USP are available as 2.5 mg (pink) and 5 mg (yellow) film-coated tablets for oral administration. The film-coated tablets contain lactose monohydrate, microcrystalline cellulose, sodium starch glycolate, magnesium stearate, hypromellose, titanium dioxide, polyethylene glycol, ferric oxide yellow (2.5 mg and 5 mg tablet), ferric oxide red (2.5 mg tablet). \n \n Zolmitriptan tablets meets USP Dissolution Test 2.\n " }

Zolmitriptan binds with high affinity to human recombinant 5-HT 1Dand 5-HT 1Breceptors, and moderate affinity for 5-HT 1Areceptors. The N-desmethyl metabolite also has high affinity for 5-HT 1B/1Dand moderate affinity for 5-HT 1Areceptors.

Migraines are likely due to local cranial vasodilatation and/or to the release of sensory neuropeptides (vasoactive intestinal peptide, substance P and calcitonin gene-related peptide) through nerve endings in the trigeminal system. The therapeutic activity of zolmitriptan tablets for the treatment of migraine headache is thought to be due to the agonist effects at the 5-HT 1B/1Dreceptors on intracranial blood vessels (including the arteriovenous anastomoses) and sensory nerves of the trigeminal system which result in cranial vessel constriction and inhibition of pro-inflammatory neuropeptide release.

Absorption, Distribution, Metabolism, and Excretion

Absorption

Zolmitriptan is well absorbed after oral administration for both zolmitriptan tablets and zolmitriptan orally disintegrating tablets. Zolmitriptan displays linear kinetics over the dose range of 2.5 to 50 mg.

The AUC and C maxof zolmitriptan are similar following administration of zolmitriptan tablets and zolmitriptan orally disintegrating tablets, but the T maxis somewhat later with zolmitriptan orally disintegrating tablets, with a median T maxof 3 hours for zolmitriptan orally disintegrating tablets compared with 1.5 hours for the zolmitriptan tablets. The AUC, C max, and T maxfor the active N-desmethyl metabolite are similar for the two formulations.

During a moderate to severe migraine attack, mean AUC 0-4and C maxfor zolmitriptan, dosed as a zolmitriptan tablet, were decreased by 40% and 25%, respectively, and mean T maxwas delayed by one-half hour compared to the same patients during a migraine free period.

Food has no significant effect on the bioavailability of zolmitriptan. No accumulation occurred on multiple dosing.

Distribution

Mean absolute bioavailability is approximately 40%. The mean apparent volume of distribution is 7.0 L/kg. Plasma protein binding of zolmitriptan is 25% over the concentration range of 10 to 1000 ng/mL.

Metabolism

Zolmitriptan is converted to an active N-desmethyl metabolite; the metabolite concentrations are about two-thirds that of zolmitriptan. Because the 5HT 1B/1Dpotency of the metabolite is 2 to 6 times that of the parent compound, the metabolite may contribute a substantial portion of the overall effect after zolmitriptan tablets administration.

Excretion

Total radioactivity recovered in urine and feces was 65% and 30% of the administered dose, respectively. About 8% of the dose was recovered in the urine as unchanged zolmitriptan. Indole acetic acid metabolite accounted for 31% of the dose, followed by N-oxide (7%) and N-desmethyl (4%) metabolites. The indole acetic acid and N-oxide metabolites are inactive.

Mean total plasma clearance is 31.5 mL/min/kg, of which one-sixth is renal clearance. The renal clearance is greater than the glomerular filtration rate suggesting renal tubular secretion.

Specific Populations

Hepatic Impairment

In patients with severe hepatic impairment, the mean C max, T max, and AUC 0-∞of zolmitriptan were increased 1.5-fold, 2-fold (2 vs. 4 hours), and 3-fold, respectively, compared to subjects with normal hepatic function. Seven out of 27 patients experienced 20 to 80 mm Hg elevations in systolic and/or diastolic blood pressure after a 10 mg zolmitriptan tablets dose. Adjust the zolmitriptan dose in patients with moderate or severe hepatic impairment [seeDosage and Administration (2.3),Use in Specific Populations (8.6)].

Renal Impairment

Clearance of zolmitriptan was reduced by 25% in patients with severe renal impairment (Cl cr≥ 5 ≤ 25 mL/min) compared to subjects with normal renal function (Cl cr≥ 70 mL/min); no significant change in clearance was observed in patients with moderate renal impairment (Cl cr≥ 26 ≤ 50 mL/min).

Age

Zolmitriptan pharmacokinetics in healthy elderly non-migraineur volunteers (age 65 - 76 years) was similar to those in younger non-migraineur volunteers (age 18 - 39 years).

Sex

Mean plasma concentrations of zolmitriptan were up to 1.5-fold higher in females than males.

Race

Retrospective analysis of pharmacokinetic data between Japanese and Caucasians revealed no significant differences.

Hypertensive Patients

No differences in the pharmacokinetics of zolmitriptan or its effects on blood pressure were seen in mild to moderate hypertensive volunteers compared with normotensive controls.

Drug Interaction Studies

All drug interaction studies were performed in healthy volunteers using a single 10 mg dose of zolmitriptan tablets and a single dose of the other drug except where otherwise noted.

MAO Inhibitors

Following one week of administration of moclobemide (150 mg twice daily), a specific MAO-A inhibitor, there was an increase of about 25% in both C maxand AUC for zolmitriptan and a 3-fold increase in the C maxand AUC of the active N-desmethyl metabolite of zolmitriptan. MAO inhibitors are contraindicated in zolmitriptan-treated patients [seeContraindications (4),Warnings and Precautions (5.7),Drug Interactions (7.2,7.4)].

Selegiline, a selective MAO-B inhibitor, at a dose of 10 mg/day for 1 week, had no effect on the pharmacokinetics of zolmitriptan and its metabolite.

Cimetidine

Following the administration of cimetidine, the half-life and AUC of zolmitriptan (5 mg dose), and its active metabolite, were approximately doubled [seeDosage and Administration (2.4),Drug Interactions (7.5)].

Fluoxetine

The pharmacokinetics of zolmitriptan, as well as its effect on blood pressure, were unaffected by 4 weeks of pretreatment with oral fluoxetine (20 mg/day).

Propranolol

C maxand AUC of zolmitriptan were increased 1.5-fold after one week of dosing with propranolol (160 mg/day). C maxand AUC of the N-desmethyl metabolite were reduced by 30% and 15%, respectively. There were no changes in blood pressure or pulse rate following administration of propranolol with zolmitriptan tablets.

Acetaminophen

A single 1 gram dose of acetaminophen did not alter the pharmacokinetics of zolmitriptan and its N-desmethyl metabolite. However, zolmitriptan tablets administration delayed the T maxof acetaminophen by one hour.

Metoclopramide

A single 10 mg dose of metoclopramide had no effect on the pharmacokinetics of zolmitriptan or its metabolites.

Oral Contraceptives

Retrospective analysis of pharmacokinetic data across studies indicated that mean C maxand AUC of zolmitriptan were increased by 30% and 50%, respectively, and T maxwas delayed by one-half hour in women taking oral contraceptives. The effect of zolmitriptan tablets on the pharmacokinetics of oral contraceptives has not been studied.

Carcinogenesis

Zolmitriptan was administered to mice and rats at doses up to 400 mg/kg/day. Mice were dosed for 85 weeks (males) and 92 weeks (females); rats were dosed for 101 weeks (males) and 86 weeks (females). There was no evidence of drug-induced tumors in mice at plasma exposures (AUC) up to approximately 700 times that in humans at the maximum recommended human dose (MRHD) of 10 mg/day. In rats, there was an increase in the incidence of thyroid follicular cell hyperplasia and thyroid follicular cell adenomas in male rats receiving 400 mg/kg/day. No increase in tumors was observed in rats at 100 mg/kg/day, a dose associated with a plasma AUC approximately 700 times that in humans at the MRHD.

Mutagenesis

Zolmitriptanwas positive in an in vitrobacterial reverse mutation (Ames) assay and in an in vitrochromosomal aberration assay in human lymphocytes. Zolmitriptan was negative in an in vitromammalian gene cell mutation (CHO/HGPRT) assay and in oral in vivomouse micronucleus assays in mouse and rat.

Impairment of Fertility

Studies of male and female rats administered zolmitriptan prior to and during mating and up to implantation showed no impairment of fertility at oral doses up to 400 mg/kg/day. The plasma exposure (AUC) at this dose was approximately 3000 times that in humans at the MRHD.

Zolmitriptan tablets

{ "type": "p", "children": [], "text": "\nZolmitriptan tablets\n" }

Theefficacy of zolmitriptan tablets in the acute treatment of migraine headaches was demonstrated in five randomized, double-blind, placebo-controlled studies (Studies 1, 2, 3, 4, and 5), of which two utilized the 1 mg dose, two utilized the 2.5 mg dose and four utilized the 5 mg dose. In Study 1, patients treated their headaches in a clinic setting. In the other studies, patients treated their headaches as outpatients. In Study 4, patients who had previously used sumatriptan were excluded, whereas in the other studies no such exclusion was applied.

{ "type": "p", "children": [], "text": "\nTheefficacy of zolmitriptan tablets in the acute treatment of migraine headaches was demonstrated in five randomized, double-blind, placebo-controlled studies (Studies 1, 2, 3, 4, and 5), of which two utilized the 1 mg dose, two utilized the 2.5 mg dose and four utilized the 5 mg dose. In Study 1, patients treated their headaches in a clinic setting. In the other studies, patients treated their headaches as outpatients. In Study 4, patients who had previously used sumatriptan were excluded, whereas in the other studies no such exclusion was applied.\n\n " }

Patients enrolled in these 5 studies were predominantly female (82%) and Caucasian (97%) with a mean age of 40 years (range 12-65). Patients were instructed to treat a moderate to severe headache. Headache response, defined as a reduction in headache severity from moderate or severe pain to mild or no pain, was assessed at 1, 2, and, in most studies, 4 hours after dosing. Associated symptoms such as nausea, photophobia, and phonophobia were also assessed. Maintenance of response was assessed for up to 24 hours post-dose. A second dose of zolmitriptan tablets or other medication was allowed 2 to 24 hours after the initial treatment for persistent and recurrent headache. The frequency and time to use of these additional treatments were also recorded. In all studies, the effect of zolmitriptan tablets was compared to placebo in the treatment of a single migraine attack.

{ "type": "p", "children": [], "text": "Patients enrolled in these 5 studies were predominantly female (82%) and Caucasian (97%) with a mean age of 40 years (range 12-65). Patients were instructed to treat a moderate to severe headache. Headache response, defined as a reduction in headache severity from moderate or severe pain to mild or no pain, was assessed at 1, 2, and, in most studies, 4 hours after dosing. Associated symptoms such as nausea, photophobia, and phonophobia were also assessed. Maintenance of response was assessed for up to 24 hours post-dose. A second dose of zolmitriptan tablets or other medication was allowed 2 to 24 hours after the initial treatment for persistent and recurrent headache. The frequency and time to use of these additional treatments were also recorded. In all studies, the effect of zolmitriptan tablets was compared to placebo in the treatment of a single migraine attack." }

In all five studies, the percentage of patients achieving headache response 2 hours after treatment was significantly greater among patients who received zolmitriptan tablets  at all doses (except for the 1 mg dose in the smallest study) compared to those who received placebo. In Studies 1 and 3, there was a statistically significant greater percentage of patients with headache response at 2 hours in the higher dose groups (2.5 and/or 5 mg) compared to the 1 mg dose group. There were no statistically significant differences between the 2.5 and 5 mg dose groups (or of doses up to 20 mg) for the primary end point of headache response at 2 hours in any study. The results of these controlled clinical studies are summarized in Table 2.

{ "type": "p", "children": [], "text": "In all five studies, the percentage of patients achieving headache response 2 hours after treatment was significantly greater among patients who received zolmitriptan tablets  at all doses (except for the 1 mg dose in the smallest study) compared to those who received placebo. In Studies 1 and 3, there was a statistically significant greater percentage of patients with headache response at 2 hours in the higher dose groups (2.5 and/or 5 mg) compared to the 1 mg dose group. There were no statistically significant differences between the 2.5 and 5 mg dose groups (or of doses up to 20 mg) for the primary end point of headache response at 2 hours in any study. The results of these controlled clinical studies are summarized in Table 2." }

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="100%"> <caption> <span>Table 2: Percentage of Patients with Headache Response (Reduction in Headache Severity from Moderate or Severe Pain to Mild or No Headache) 2 Hours Following Treatment in Studies 1 through 5</span> </caption> <col width="20.04%"/> <col width="20.04%"/> <col width="20.04%"/> <col width="20.04%"/> <col width="19.82%"/> <tfoot> <tr class="First Last"> <td colspan="30">* Study 1 was the only study in which patients treated the headache in a clinic setting. <br/> † n = number of patients randomized <br/> ‡ NA = not applicable <br/> § P&lt;0.05 in comparison with placebo. <br/> ¶ P&lt;0.05 in comparison with 1 mg. <br/> # Study 4 was the only study where patients were excluded who had previously used sumatriptan. </td> </tr> </tfoot> <tbody class="Headless"> <tr class="Botrule First"> <td class="Lrule Rrule" valign="top"> <br/> </td><td align="center" class="Rrule" valign="top">Placebo <br/> <br/> </td><td align="center" class="Rrule" valign="top">Zolmitriptan tablets <br/> 1 mg <br/> </td><td align="center" class="Rrule" valign="top">Zolmitriptan tablets <br/> 2.5 mg <br/> </td><td align="center" class="Rrule" valign="top">Zolmitriptan tablets <br/> 5 mg <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Study 1 <span class="Sup">*</span> <br/> </td><td align="center" class="Rrule" valign="top">16% <br/> (n <span class="Sup">†</span>=19) <br/> </td><td align="center" class="Rrule" valign="top">27% <br/> (n=22) <br/> </td><td align="center" class="Rrule" valign="top">NA <span class="Sup">‡</span> <br/> </td><td align="center" class="Rrule" valign="top">60% <span class="Sup">§¶</span> <br/> (n=20) <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Study 2 <br/> </td><td align="center" class="Rrule" valign="top">19% <br/> (n=88) <br/> </td><td align="center" class="Rrule" valign="top">NA <br/> </td><td align="center" class="Rrule" valign="top">NA <br/> </td><td align="center" class="Rrule" valign="top">66% <span class="Sup">§</span> <br/> (n=179) <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Study 3 <br/> </td><td align="center" class="Rrule" valign="top">34% <br/> (n=121) <br/> </td><td align="center" class="Rrule" valign="top">50% <span class="Sup">§</span> <br/> (n=140) <br/> </td><td align="center" class="Rrule" valign="top">65% <span class="Sup">§¶</span> <br/> (n=260) <br/> </td><td align="center" class="Rrule" valign="top">67% <span class="Sup">§¶</span> <br/> (n=245) <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Study 4 <span class="Sup">#</span> <br/> </td><td align="center" class="Rrule" valign="top">44% <br/> (n=55) <br/> </td><td align="center" class="Rrule" valign="top">NA <br/> </td><td align="center" class="Rrule" valign="top">NA <br/> </td><td align="center" class="Rrule" valign="top">59% <span class="Sup">§</span> <br/> (n=491) <br/> </td> </tr> <tr class="Last"> <td class="Lrule Rrule" valign="top">Study 5 <br/> </td><td align="center" class="Rrule" valign="top">36% <br/> (n=92) <br/> </td><td align="center" class="Rrule" valign="top">NA <br/> <br/> </td><td align="center" class="Rrule" valign="top">62% <span class="Sup">§</span> <br/> (n=178) <br/> </td><td align="center" class="Rrule" valign="top">NA <br/> </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table border=\"0\" cellpadding=\"0\" cellspacing=\"0\" width=\"100%\">\n<caption>\n<span>Table 2: Percentage of Patients with Headache Response (Reduction in Headache Severity from Moderate or Severe Pain to Mild or No Headache) 2 Hours Following Treatment in Studies 1 through 5</span>\n</caption>\n<col width=\"20.04%\"/>\n<col width=\"20.04%\"/>\n<col width=\"20.04%\"/>\n<col width=\"20.04%\"/>\n<col width=\"19.82%\"/>\n<tfoot>\n<tr class=\"First Last\">\n<td colspan=\"30\">* Study 1 was the only study in which patients treated the headache in a clinic setting. \n <br/> † n = number of patients randomized \n <br/> ‡ NA = not applicable \n <br/> § P&lt;0.05 in comparison with placebo. \n <br/> ¶ P&lt;0.05 in comparison with 1 mg. \n <br/> # Study 4 was the only study where patients were excluded who had previously used sumatriptan.\n </td>\n</tr>\n</tfoot>\n<tbody class=\"Headless\">\n<tr class=\"Botrule First\">\n<td class=\"Lrule Rrule\" valign=\"top\">\n<br/>\n</td><td align=\"center\" class=\"Rrule\" valign=\"top\">Placebo \n <br/>\n<br/>\n</td><td align=\"center\" class=\"Rrule\" valign=\"top\">Zolmitriptan tablets \n <br/> 1 mg \n <br/>\n</td><td align=\"center\" class=\"Rrule\" valign=\"top\">Zolmitriptan tablets \n <br/> 2.5 mg \n <br/>\n</td><td align=\"center\" class=\"Rrule\" valign=\"top\">Zolmitriptan tablets \n <br/> 5 mg \n <br/>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td class=\"Lrule Rrule\" valign=\"top\">Study 1\n \n <span class=\"Sup\">*</span>\n<br/>\n</td><td align=\"center\" class=\"Rrule\" valign=\"top\">16% \n <br/> (n\n \n <span class=\"Sup\">†</span>=19) \n <br/>\n</td><td align=\"center\" class=\"Rrule\" valign=\"top\">27% \n <br/> (n=22) \n <br/>\n</td><td align=\"center\" class=\"Rrule\" valign=\"top\">NA\n \n <span class=\"Sup\">‡</span>\n<br/>\n</td><td align=\"center\" class=\"Rrule\" valign=\"top\">60%\n \n <span class=\"Sup\">§¶</span>\n<br/> (n=20) \n <br/>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td class=\"Lrule Rrule\" valign=\"top\">Study 2 \n <br/>\n</td><td align=\"center\" class=\"Rrule\" valign=\"top\">19% \n <br/> (n=88) \n <br/>\n</td><td align=\"center\" class=\"Rrule\" valign=\"top\">NA \n <br/>\n</td><td align=\"center\" class=\"Rrule\" valign=\"top\">NA \n <br/>\n</td><td align=\"center\" class=\"Rrule\" valign=\"top\">66%\n \n <span class=\"Sup\">§</span>\n<br/> (n=179) \n <br/>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td class=\"Lrule Rrule\" valign=\"top\">Study 3 \n <br/>\n</td><td align=\"center\" class=\"Rrule\" valign=\"top\">34% \n <br/> (n=121) \n <br/>\n</td><td align=\"center\" class=\"Rrule\" valign=\"top\">50%\n \n <span class=\"Sup\">§</span>\n<br/> (n=140) \n <br/>\n</td><td align=\"center\" class=\"Rrule\" valign=\"top\">65%\n \n <span class=\"Sup\">§¶</span>\n<br/> (n=260) \n <br/>\n</td><td align=\"center\" class=\"Rrule\" valign=\"top\">67%\n \n <span class=\"Sup\">§¶</span>\n<br/> (n=245) \n <br/>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td class=\"Lrule Rrule\" valign=\"top\">Study 4\n \n <span class=\"Sup\">#</span>\n<br/>\n</td><td align=\"center\" class=\"Rrule\" valign=\"top\">44% \n <br/> (n=55) \n <br/>\n</td><td align=\"center\" class=\"Rrule\" valign=\"top\">NA \n <br/>\n</td><td align=\"center\" class=\"Rrule\" valign=\"top\">NA \n <br/>\n</td><td align=\"center\" class=\"Rrule\" valign=\"top\">59%\n \n <span class=\"Sup\">§</span>\n<br/> (n=491) \n <br/>\n</td>\n</tr>\n<tr class=\"Last\">\n<td class=\"Lrule Rrule\" valign=\"top\">Study 5 \n <br/>\n</td><td align=\"center\" class=\"Rrule\" valign=\"top\">36% \n <br/> (n=92) \n <br/>\n</td><td align=\"center\" class=\"Rrule\" valign=\"top\">NA \n <br/>\n<br/>\n</td><td align=\"center\" class=\"Rrule\" valign=\"top\">62%\n \n <span class=\"Sup\">§</span>\n<br/> (n=178) \n <br/>\n</td><td align=\"center\" class=\"Rrule\" valign=\"top\">NA \n <br/>\n</td>\n</tr>\n</tbody>\n</table></div>" }

The estimated probability of achieving an initial headache response by 4 hours following treatment in pooled Studies 2, 3, and 5 is depicted in Figure 1.

{ "type": "p", "children": [], "text": "The estimated probability of achieving an initial headache response by 4 hours following treatment in pooled Studies 2, 3, and 5 is depicted in Figure 1." }

Figure 1: Estimated Probability of Achieving Initial Headache Response (Reduction in Headache Severity from Moderate or Severe Pain to Mild or No Headache) Within 4 Hours of Treatment in Pooled Studies 2, 3, and 5*

{ "type": "p", "children": [], "text": "\nFigure 1: Estimated Probability of Achieving Initial Headache Response (Reduction in Headache Severity from Moderate or Severe Pain to Mild or No Headache) Within 4 Hours of Treatment in Pooled Studies 2, 3, and 5*\n" }

*In this Kaplan-Meier plot, the averages displayed are based on pooled data from 3 placebo controlled outpatient trials. Patients not achieving headache response or taking additional treatment prior to 4 hours were censored at 4 hours.

{ "type": "p", "children": [], "text": "*In this Kaplan-Meier plot, the averages displayed are based on pooled data from 3 placebo controlled outpatient trials. Patients not achieving headache response or taking additional treatment prior to 4 hours were censored at 4 hours." }

For patients with migraine associated photophobia, phonophobia, and nausea at baseline, there was a decreased incidence of these symptoms following administration of zolmitriptan tablets as compared with placebo.

{ "type": "p", "children": [], "text": "For patients with migraine associated photophobia, phonophobia, and nausea at baseline, there was a decreased incidence of these symptoms following administration of zolmitriptan tablets as compared with placebo." }

Two to 24 hours following the initial dose of study treatment, patients were allowed to use additional treatment for pain relief in the form of a second dose of study treatment or other medication. The estimated probability of patients taking a second dose or other medication for migraine over the 24 hours following the initial dose of study treatment is summarized in Figure 2.

{ "type": "p", "children": [], "text": "Two to 24 hours following the initial dose of study treatment, patients were allowed to use additional treatment for pain relief in the form of a second dose of study treatment or other medication. The estimated probability of patients taking a second dose or other medication for migraine over the 24 hours following the initial dose of study treatment is summarized in Figure 2." }

Figure 2: The Estimated Probability of Patients Taking a Second Dose or Other Medication for Migraines over the 24 Hours Following the Initial Dose of Study Treatment in Pooled Studies 2, 3, and 5*

{ "type": "p", "children": [], "text": "\nFigure 2: The Estimated Probability of Patients Taking a Second Dose or Other Medication for Migraines over the 24 Hours Following the Initial Dose of Study Treatment in Pooled Studies 2, 3, and 5*\n" }

*In this Kaplan-Meier plot, patients not using additional treatments were censored at 24 hours. The plot includes both patients who had headache response at 2 hours and those who had no response to the initial dose. The studies did not allow taking additional doses of study medication within 2 hours post-dose.

{ "type": "p", "children": [], "text": "*In this Kaplan-Meier plot, patients not using additional treatments were censored at 24 hours. The plot includes both patients who had headache response at 2 hours and those who had no response to the initial dose. The studies did not allow taking additional doses of study medication within 2 hours post-dose." }

The efficacy of zolmitriptan tablets was unaffected by presence of aura; duration of headache prior to treatment; relationship to menses; gender, age, or weight of the patient; pre-treatment nausea or concomitant use of common migraine prophylactic drugs.

{ "type": "p", "children": [], "text": "The efficacy of zolmitriptan tablets was unaffected by presence of aura; duration of headache prior to treatment; relationship to menses; gender, age, or weight of the patient; pre-treatment nausea or concomitant use of common migraine prophylactic drugs." }

2.5 mg Tablets- Pink, round, biconvex, film-coated tablets with "ZL 1" engraved on one side and break line on other side are supplied in cartons containing 6 tablets (NDC 76420-336-06 relabeled from NDC 27241-021-68).

{ "type": "p", "children": [], "text": "\n2.5 mg Tablets- Pink, round, biconvex, film-coated tablets with \"ZL 1\" engraved on one side and break line on other side are supplied in cartons containing 6 tablets (NDC 76420-336-06 relabeled from NDC 27241-021-68).\n " }

5 mg Tablets- Yellow, round, biconvex, film-coated tablets with "ZL 2" engraved on one side and plain on other side are supplied in cartons containing 3 tablets (NDC 76420-337-03 relabeled from NDC 27241-022-38).

{ "type": "p", "children": [], "text": "\n5 mg Tablets- Yellow, round, biconvex, film-coated tablets with \"ZL 2\" engraved on one side and plain on other side are supplied in cartons containing 3 tablets (NDC 76420-337-03 relabeled from NDC 27241-022-38).\n " }

Store zolmitriptan tablets at 20-25°C (68-77°F) [see USP Controlled Room Temperature]. Protect from light and moisture.

{ "type": "p", "children": [], "text": "Store zolmitriptan tablets at 20-25°C (68-77°F) [see USP Controlled Room Temperature]. Protect from light and moisture." }

Advise the patient to read the FDA-approved patient labeling (Patient Information).

{ "type": "p", "children": [], "text": "Advise the patient to read the FDA-approved patient labeling (Patient Information)." }

Myocardial Ischemia and/or Infarction, Prinzmetal’s Angina, Other Vasospastic Reactions, and Cerebrovascular Events

{ "type": "p", "children": [], "text": "\nMyocardial Ischemia and/or Infarction, Prinzmetal’s Angina, Other Vasospastic Reactions, and Cerebrovascular Events\n" }

Inform patients that zolmitriptan tablets may cause serious cardiovascular adverse reactions such as myocardial infarction or stroke, which may result in hospitalization and even death. Although serious cardiovascular reactions can occur without warning symptoms, instruct patients to be alert for the signs and symptoms of chest pain, shortness of breath, weakness, slurring of speech, and instruct them to ask for medical advice when observing any indicative sign or symptoms. Instruct patients to seek medical advice if they have symptoms of other vasospastic reactions [seeWarnings and Precautions (5.1,5.2,5.4,5.5)].

{ "type": "p", "children": [], "text": "Inform patients that zolmitriptan tablets may cause serious cardiovascular adverse reactions such as myocardial infarction or stroke, which may result in hospitalization and even death. Although serious cardiovascular reactions can occur without warning symptoms, instruct patients to be alert for the signs and symptoms of chest pain, shortness of breath, weakness, slurring of speech, and instruct them to ask for medical advice when observing any indicative sign or symptoms. Instruct patients to seek medical advice if they have symptoms of other vasospastic reactions\n \n [seeWarnings and Precautions (5.1,5.2,5.4,5.5)].\n\n " }

Medication Overuse Headache

{ "type": "p", "children": [], "text": "\nMedication Overuse Headache\n" }

Inform patients that use of drugs to treat acute migraines for 10 or more days per month may lead to an exacerbation of headache, and encourage patients to record headache frequency and drug use (e.g., by keeping a headache diary) [seeWarnings and Precautions (5.6)].

{ "type": "p", "children": [], "text": "Inform patients that use of drugs to treat acute migraines for 10 or more days per month may lead to an exacerbation of headache, and encourage patients to record headache frequency and drug use (e.g., by keeping a headache diary)\n \n [seeWarnings and Precautions (5.6)].\n\n " }

Serotonin Syndrome

{ "type": "p", "children": [], "text": "\nSerotonin Syndrome\n" }

Inform patients about the risk of serotonin syndrome with the use of zolmitriptan tablets or other triptans, particularly during combined use with selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs) [seeWarnings and Precautions (5.7)].

{ "type": "p", "children": [], "text": "Inform patients about the risk of serotonin syndrome with the use of zolmitriptan tablets or other triptans, particularly during combined use with selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs)\n \n [seeWarnings and Precautions (5.7)].\n\n " }

Pregnancy

{ "type": "p", "children": [], "text": "\nPregnancy\n" }

Advise patients to notify their healthcare provider if they are pregnant or plan to become pregnant.

{ "type": "p", "children": [], "text": "Advise patients to notify their healthcare provider if they are pregnant or plan to become pregnant." }

Lactation

{ "type": "p", "children": [], "text": "\nLactation\n" }

Advise patients to notify their healthcare provider if they are breastfeeding or plan to breastfeed [see Use in Specific Populations ( 8.2)].

{ "type": "p", "children": [], "text": "Advise patients to notify their healthcare provider if they are breastfeeding or plan to breastfeed\n \n [see Use in Specific Populations (\n \n 8.2)].\n \n \n" }

Patient InformationZolmitriptan (zole’’ mi trip’ tan) Tablets, USP

{ "type": "p", "children": [], "text": "\nPatient InformationZolmitriptan (zole’’ mi trip’ tan) Tablets, USP\n" }

Please read this information before you start taking zolmitriptan tablets and each time you renew your prescription just in case anything has changed. Remember, this summary does not take the place of discussions with your doctor. You and your doctor should discuss zolmitriptan tablets when you start taking your medication and at regular checkups.

{ "type": "p", "children": [], "text": "Please read this information before you start taking zolmitriptan tablets and each time you renew your prescription just in case anything has changed. Remember, this summary does not take the place of discussions with your doctor. You and your doctor should discuss zolmitriptan tablets when you start taking your medication and at regular checkups." }

What are zolmitriptan tablets?

{ "type": "p", "children": [], "text": "\nWhat are zolmitriptan tablets?\n" }

Zolmitriptan tablets are a prescription medication used to treat migraine headaches in adults. Zolmitriptan tablets are not for other types of headaches. The safety and efficacy of zolmitriptan tablets in patients under 18 have not been established.

{ "type": "p", "children": [], "text": "Zolmitriptan tablets are a prescription medication used to treat migraine headaches in adults. Zolmitriptan tablets are not for other types of headaches. The safety and efficacy of zolmitriptan tablets in patients under 18 have not been established." }

What is a Migraine Headache?

{ "type": "p", "children": [], "text": "\nWhat is a Migraine Headache?\n" }

Migraine is an intense, throbbing headache. You may have pain on one or both sides of your head. You may have nausea and vomiting, and be sensitive to light and noise. The pain and symptoms of a migraine headache can be worse than a common headache. Some women get migraines around the time of their menstrual period. Some people have visual symptoms before the headache, such as flashing lights or wavy lines, called an aura.

{ "type": "p", "children": [], "text": "Migraine is an intense, throbbing headache. You may have pain on one or both sides of your head. You may have nausea and vomiting, and be sensitive to light and noise. The pain and symptoms of a migraine headache can be worse than a common headache. Some women get migraines around the time of their menstrual period. Some people have visual symptoms before the headache, such as flashing lights or wavy lines, called an aura." }

How does zolmitriptan tablets work?

{ "type": "p", "children": [], "text": "\nHow does zolmitriptan tablets work?\n" }

Treatment with zolmitriptan tablets reduces swelling of blood vessels surrounding the brain. This swelling is associated with the headache pain of a migraine attack. Zolmitriptan tablets blocks the release of substances from nerve endings that cause more pain and other symptoms like nausea, and sensitivity to light and sound. It is thought that these actions contribute to relief of your symptoms by zolmitriptan tablets.

{ "type": "p", "children": [], "text": "Treatment with zolmitriptan tablets reduces swelling of blood vessels surrounding the brain. This swelling is associated with the headache pain of a migraine attack. Zolmitriptan tablets blocks the release of substances from nerve endings that cause more pain and other symptoms like nausea, and sensitivity to light and sound. It is thought that these actions contribute to relief of your symptoms by zolmitriptan tablets." }

Who should not take zolmitriptan tablets?

{ "type": "p", "children": [], "text": "\nWho should not take zolmitriptan tablets?\n" }

Do not take zolmitriptan tablets if you:

{ "type": "p", "children": [], "text": "\nDo not take zolmitriptan tablets if you:\n" }

{ "type": "ul", "children": [ "Have heart disease or a history of heart disease", "Have uncontrolled high blood pressure", "Have hemiplegic or basilar migraine (if you are not sure about this, ask your doctor)", "Have serious liver problems", "Have taken any of the following medicines in the last 24 hours: other “triptans” like almotriptan (AXERT\n \n ®), eletriptan (RELPAX\n \n ®), frovatriptan (FROVA\n \n ®), naratriptan(AMERGE\n \n ®), rizatriptan (MAXALT\n \n ®), sumatriptan (IMITREX\n \n ®), sumatriptan/naproxen (TREXIMET\n \n ®); ergotamines like BELLERGAL-S\n \n ®, CAFERGOT\n \n ®, ERGOMAR\n \n ®,WIGRAINE\n \n ®; dihydroergotamine like D.H.E. 45\n \n ®or MIGRANAL\n \n ®; or methysergide (SANSERT\n \n ®). These medications have side effects similar to zolmitriptan tablets.\n \n ", "Have taken monoamine oxidase (MAO) inhibitors such as phenelzine sulfate (NARDIL\n \n ®) or tranylcypromine sulfate (PARNATE\n \n ®) for depression or other conditions within the last 2 weeks.\n \n ", "Are allergic to zolmitriptan tablets or any of its ingredients. The active ingredient is zolmitriptan. The inactive ingredients are listed at the end of this leaflet." ], "text": "" }

Tell your doctor about all the medicines you take or plan to take, including prescription and non-prescription medicines, supplements, and herbal remedies.

{ "type": "p", "children": [], "text": "Tell your doctor about all the medicines you take or plan to take, including prescription and non-prescription medicines, supplements, and herbal remedies." }

Tell your doctor if you are taking selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs), two types of drugs for depression or other disorders. Common SSRIs are CELEXA ®(citalopram HBr), LEXAPRO ®(escitalopram oxalate), PAXIL ®(paroxetine), PROZAC ®(fluoxetine), SYMBYAX ®(olanzapine/fluoxetine), ZOLOFT ®(sertraline), SARAFEM ®(fluoxetine) and LUVOX ®(fluvoxamine). Common SNRIs are CYMBALTA ®(duloxetine) and EFFEXOR ®(venlafaxine). Your doctor will decide if you can take zolmitriptan tablets with your other medicines.

{ "type": "p", "children": [], "text": "Tell your doctor if you are taking selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs), two types of drugs for depression or other disorders. Common SSRIs are CELEXA\n \n ®(citalopram HBr), LEXAPRO\n \n ®(escitalopram oxalate), PAXIL\n \n ®(paroxetine), PROZAC\n \n ®(fluoxetine), SYMBYAX\n \n ®(olanzapine/fluoxetine), ZOLOFT\n \n ®(sertraline), SARAFEM\n \n ®(fluoxetine) and LUVOX\n \n ®(fluvoxamine). Common SNRIs are CYMBALTA\n \n ®(duloxetine) and EFFEXOR\n \n ®(venlafaxine). Your doctor will decide if you can take zolmitriptan tablets with your other medicines.\n\n " }

Tell your doctor if you know that you have any of the following: risk factors for heart disease like high cholesterol, diabetes, smoking, obesity (overweight), menopause, or a family history of heart disease or stroke.

{ "type": "p", "children": [], "text": "Tell your doctor if you know that you have any of the following: risk factors for heart disease like high cholesterol, diabetes, smoking, obesity (overweight), menopause, or a family history of heart disease or stroke." }

Tell your doctor if you are pregnant or plan to become pregnant. It is not known if zolmitriptan tablets will harm your unborn baby.

{ "type": "p", "children": [], "text": "Tell your doctor if you are pregnant or plan to become pregnant. It is not known if zolmitriptan tablets will harm your unborn baby." }

Tell your doctor if you are breast feeding or plan to breast feed. It is not known if zolmitriptan passes into your breast milk. Talk to your doctor about the best way to feed your baby while using zolmitriptan tablets.

{ "type": "p", "children": [], "text": "Tell your doctor if you are breast feeding or plan to breast feed. It is not known if zolmitriptan passes into your breast milk. Talk to your doctor about the best way to feed your baby while using zolmitriptan tablets." }

How should I take zolmitriptan tablets?

{ "type": "p", "children": [], "text": "\nHow should I take zolmitriptan tablets?\n" }

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What are the possible side effects of zolmitriptan tablets?

{ "type": "p", "children": [], "text": "\nWhat are the possible side effects of zolmitriptan tablets?\n" }

Zolmitriptan tablets are generally well tolerated. As with any medicine, people taking zolmitriptan tablets may have side effects. The side effects are usually mild and do not last long.

{ "type": "p", "children": [], "text": "Zolmitriptan tablets are generally well tolerated. As with any medicine, people taking zolmitriptan tablets may have side effects. The side effects are usually mild and do not last long." }

The most common side effects of zolmitriptan tablets are:

{ "type": "p", "children": [], "text": "The most common side effects of zolmitriptan tablets are:" }

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In very rare cases, patients taking triptans may experience serious side effects, such as heart attacks, high blood pressure, stroke, or serious allergic reactions. Extremely rarely, patients have died. Call your doctor right away if you have any of the following problems after taking zolmitriptan tablets:

{ "type": "p", "children": [], "text": "In very rare cases, patients taking triptans may experience serious side effects, such as heart attacks, high blood pressure, stroke, or serious allergic reactions. Extremely rarely, patients have died.\n \n Call your doctor right away if you have any of the following problems after taking zolmitriptan tablets:\n" }

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Some people may have a reaction called serotonin syndrome, which can be life-threatening, when they use zolmitriptan tablets. In particular, this reaction may occur when they use zolmitriptan tablets together with certain types of antidepressants known as SSRIs or SNRIs. Symptoms may include mental changes (hallucinations, agitation, coma), fast heartbeat, changes in blood pressure, high body temperature or sweating, tight muscles, trouble walking, nausea, vomiting, and diarrhea. Call your doctor immediately if you have any of these symptoms after taking zolmitriptan tablets.

{ "type": "p", "children": [], "text": "Some people may have a reaction called serotonin syndrome, which can be life-threatening, when they use zolmitriptan tablets. In particular, this reaction may occur when they use zolmitriptan tablets together with certain types of antidepressants known as SSRIs or SNRIs. Symptoms may include mental changes (hallucinations, agitation, coma), fast heartbeat, changes in blood pressure, high body temperature or sweating, tight muscles, trouble walking, nausea, vomiting, and diarrhea. Call your doctor immediately if you have any of these symptoms after taking zolmitriptan tablets." }

This is not a complete list of side effects. Talk to your doctor if you develop any symptoms that concern you. You can also contact FDA to report side effects at 1-800-FDA-1088 or www.fda.gov/medwatch

{ "type": "p", "children": [], "text": "\nThis is not a complete list of side effects. Talk to your doctor if you develop any symptoms that concern you. \n You can also contact FDA to report side effects at 1-800-FDA-1088 or www.fda.gov/medwatch\n \n" }

What to do in case of an overdose?

{ "type": "p", "children": [], "text": "\nWhat to do in case of an overdose?\n" }

Call your doctor or poison control center or go to the nearest hospital emergency room.

{ "type": "p", "children": [], "text": "Call your doctor or poison control center or go to the nearest hospital emergency room." }

General advice about zolmitriptan tablets

{ "type": "p", "children": [], "text": "\nGeneral advice about zolmitriptan tablets\n" }

Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not use zolmitriptan tablets for a condition for which it was not prescribed. Do not give zolmitriptan tablets to other people, even if they have the same symptoms as you. People may be harmed if they take medicines that have not been prescribed for them.

{ "type": "p", "children": [], "text": "Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not use zolmitriptan tablets for a condition for which it was not prescribed. Do not give zolmitriptan tablets to other people, even if they have the same symptoms as you. People may be harmed if they take medicines that have not been prescribed for them." }

This leaflet summarizes the most important information about zolmitriptan tablets. If you would like more information about zolmitriptan tablets talk to your doctor. You can ask your doctor or pharmacist for information on zolmitriptan tablets that is written for healthcare professionals.

{ "type": "p", "children": [], "text": "This leaflet summarizes the most important information about zolmitriptan tablets. If you would like more information about zolmitriptan tablets talk to your doctor. You can ask your doctor or pharmacist for information on zolmitriptan tablets that is written for healthcare professionals." }

What are the ingredients in zolmitriptan tablets?

{ "type": "p", "children": [], "text": "\nWhat are the ingredients in zolmitriptan tablets?\n" }

Zolmitriptan tablets

{ "type": "p", "children": [], "text": "Zolmitriptan tablets" }

Active ingredient: zolmitriptan

{ "type": "p", "children": [], "text": "Active ingredient: zolmitriptan" }

Inactive ingredients:

{ "type": "p", "children": [], "text": "Inactive ingredients:" }

lactose monohydrate, microcrystalline cellulose, sodium starch glycolate, magnesium stearate, hypromellose, titanium dioxide, polyethylene glycol, ferric oxide yellow (2.5 mg and 5 mg tablet), ferric oxide red (2.5 mg tablet).

{ "type": "p", "children": [], "text": "lactose monohydrate, microcrystalline cellulose, sodium starch glycolate, magnesium stearate, hypromellose, titanium dioxide, polyethylene glycol, ferric oxide yellow (2.5 mg and 5 mg tablet), ferric oxide red (2.5 mg tablet)." }

Store zolmitriptan tablets at 20-25°C (68-77°F) [see USP Controlled Room Temperature] and away from children. Protect from light and moisture. Discard when expired.

{ "type": "p", "children": [], "text": "Store zolmitriptan tablets at 20-25°C (68-77°F) [see USP Controlled Room Temperature] and away from children. Protect from light and moisture. Discard when expired." }

Brands mentioned are trademarks of their respective owners and are not trademarks of the Ajanta Pharma Limited. The makers of these brands are not affiliated with Ajanta Pharma Limited or its products.

{ "type": "p", "children": [], "text": "Brands mentioned are trademarks of their respective owners and are not trademarks of the Ajanta Pharma Limited. The makers of these brands are not affiliated with Ajanta Pharma Limited or its products." }

Relabeled by:

{ "type": "p", "children": [], "text": "\nRelabeled by:\n" }

Enovachem PHARMACEUTICALS

{ "type": "p", "children": [], "text": "Enovachem PHARMACEUTICALS" }

Torrance, CA 90501

{ "type": "p", "children": [], "text": "Torrance, CA 90501" }